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Chen Y, Zhang D, Li J, Sun Y, Wang J, Xi L. SNS‑032 combined with decitabine induces caspase‑3/gasdermin E‑dependent pyroptosis in breast cancer cells. Oncol Lett 2025; 29:202. [PMID: 40070781 PMCID: PMC11894506 DOI: 10.3892/ol.2025.14948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/13/2025] [Indexed: 03/14/2025] Open
Abstract
SNS-032 is a synthetic compound that specifically inhibits cyclin-dependent kinases 2, 7 and 9. Its primary anticancer activity involves cell cycle arrest, which prevents tumor cell growth. However, there are limited reports on whether SNS-032 induces pyroptosis, a novel inflammation-mediated programmed cell death pathway in breast cancer (BC). The present study demonstrated that SNS-032 treatment decreased cell viability by inducing pyroptosis in BC cells. Typical morphological indications of pyroptosis were observed, including cell swelling and destruction of cell membrane integrity, leading the release of adenosine 5'-triphosphate and lactate dehydrogenase. Furthermore, the expression of caspase-3, the N terminus of gasdermin E (GSDME) and B-cell lymphoma-2 (BCL-2)-associated X protein increased, whereas expression of BCL-2 decreased. In addition, Z-DEVD-FMK, a specific caspase-3 inhibitor, markedly alleviated pyroptosis triggered by SNS-032. These findings suggested that SNS-032 induced caspase-3/GSDME-dependent pyroptosis. Furthermore, the present study demonstrated that decitabine (DAC), a DNA methyltransferase inhibitor, upregulated the expression of GSDME protein and enhanced SNS-032-induced caspase-3/GSDME-dependent pyroptosis in BC cells. In conclusion, these results suggest that caspase-3/GSDME-induced pyroptosis can be facilitated by SNS-032 treatment in BC cells, and DAC has the potential to enhance SNS-032-induced pyroptosis by increasing GSDME expression. This mechanistic insight indicates that SNS-032 is a promising therapeutic agent for BC treatment.
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Affiliation(s)
- Yuxin Chen
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Danya Zhang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Jie Li
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yue Sun
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Jing Wang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Ling Xi
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Chen W, Zhuang X, Chen Y, Yang H, Shen L, Feng S, Min W, Yuan K, Yang P. Recent advances in regulating the cell cycle through inhibiting CDKs for cancer treatment. Chin J Nat Med 2025; 23:286-298. [PMID: 40122659 DOI: 10.1016/s1875-5364(25)60846-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/11/2024] [Accepted: 06/29/2024] [Indexed: 03/25/2025]
Abstract
The inhibition of cyclin-dependent kinases (CDKs) is considered a promising strategy for cancer treatment due to their role in cell cycle regulation. However, CDK inhibitors with no selectivity among CDK families have not been approved. A CDK inhibitor with high selectivity for CDK4/6 exhibited significant treatment effects on breast cancer and has become a heavy bomb on the market. Subsequently, resistance gradually decreased the efficacy of selective CDK4/6 inhibitors in breast cancer treatment. In this review, we first introduce the development of selective CDK4/6 inhibitors and then explain the role of CDK2 activation in inducing resistance to CDK4/6 inhibitors. Moreover, we focused on the development of CDK2/4/6 inhibitors and selective CDK2 inhibitors, which will aid in the discovery of novel CDK inhibitors targeting the cell cycle in the future.
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Affiliation(s)
- Weijiao Chen
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xujie Zhuang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yuanyuan Chen
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Huanaoyu Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Linhu Shen
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Sikai Feng
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Wenjian Min
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Kai Yuan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Peng Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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3
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House I, Valore-Caplan M, Maris E, Falchook GS. Cyclin Dependent Kinase 2 (CDK2) Inhibitors in Oncology Clinical Trials: A Review. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2025; 8:47-54. [PMID: 39811424 PMCID: PMC11728386 DOI: 10.36401/jipo-24-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 09/28/2024] [Accepted: 10/02/2024] [Indexed: 01/16/2025]
Abstract
Cyclin dependent kinase 2 (CDK2) is responsible for enforcing progression through the G1-S phase transition. Mutations and alterations in the CDK2 signaling pathway are associated with various cancers, most commonly breast, ovarian, prostate, leukemia, and lymphoma. CDK2 inhibitors have shown promising preclinical and early clinical results, and this class of agents may be most effective against cancers with cyclin E overactivity. Common side effects observed include nausea, vomiting, diarrhea, anemia, and fatigue. This clinical review summarizes past and current CDK2 inhibitors in clinical trials.
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Affiliation(s)
- Isabelle House
- Sarah Cannon Research Institute at HealthONE, Denver, CO, USA
| | | | - Elijah Maris
- Sarah Cannon Research Institute at HealthONE, Denver, CO, USA
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Pellarin I, Dall'Acqua A, Favero A, Segatto I, Rossi V, Crestan N, Karimbayli J, Belletti B, Baldassarre G. Cyclin-dependent protein kinases and cell cycle regulation in biology and disease. Signal Transduct Target Ther 2025; 10:11. [PMID: 39800748 PMCID: PMC11734941 DOI: 10.1038/s41392-024-02080-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/16/2024] [Accepted: 11/13/2024] [Indexed: 01/18/2025] Open
Abstract
Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.
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Affiliation(s)
- Ilenia Pellarin
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Alessandra Dall'Acqua
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Andrea Favero
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Ilenia Segatto
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Valentina Rossi
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Nicole Crestan
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Javad Karimbayli
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Barbara Belletti
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Gustavo Baldassarre
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy.
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5
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Malarvannan M, Unnikrishnan S, Monohar S, Ravichandiran V, Paul D. Design and optimization strategies of PROTACs and its Application, Comparisons to other targeted protein degradation for multiple oncology therapies. Bioorg Chem 2025; 154:107984. [PMID: 39591691 DOI: 10.1016/j.bioorg.2024.107984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/04/2024] [Accepted: 11/17/2024] [Indexed: 11/28/2024]
Abstract
Recent years have witnessed notable breakthroughs in the field of biotherapeutics. Proteolysis Targeting Chimeras (PROTACs) are novel molecules which used to degrade particular proteins despite the blockage by small drug molecules, which leads to a predicted therapeutic activity. This is a unique finding, especially at the cellular level targets degradations. Clinical trials and studies on PROTACs are in progress for oncology indications for demonstration of high potency and activity. PROTAC molecules are having excellent tissue distribution properties and their capacity to mutate the proteins and target overexpressed. This concept has attained wide attention from modern researchers in oncological drug discovery with particular physical qualities not offered by other therapeutic approaches. The modular nature of the PROTACs enables their methodical optimization and logical design. A thorough review was conducted in order to delve deeper into the subject and gain a better understanding of its development, computational supports, important factors for the optimization of developed PROTAC candidates, pharmacokinetic and pharmacodynamic (PK-PD) aspects, safety risks such as the degradation of undesired proteins, and other PROTAC-related issues and their target immunotherapeutic response. Furthermore discussed about the benefits, possible challenges, viewpoints, comparison with other targeted protein degraders (LYTACs, AUTOTACs) and the most current research results of PROTACs technology in multiple oncology therapies. Abbreviations: PROTACs, Proteolysis Targeting Chimeras; PK, Pharmacokinetic; PD, Pharmacodynamic; MetAP-2, (methionine aminopeptidase 2); BCL6, B-cell lymphoma 6; GCN5, General Control Nonderepressible 5; BKT, Bruton's tyrosine kinase; BET, Bromodomain and extra-terminal; AR, Androgen or Androgen receptor; ER, Estrogen or Estrogen receptor; FDA, Food and Drug Administration; mCRPC, Metastatic castration-resistant prostate cancer; STAT3, Signal Transducer and Activator of Transcription 3; FAK, Focal adhesion kinase; POI, Protein of interest; PEG, Polyethylene glycol; UPS, Ubiquitin-Proteasome System; VHL, Von Hippel-Lindau; CRBN, Cereblon; MDM2, Mouse Double Minute 2 homologue; cIAP, Cellular Inhibitor of Apoptosis; RNF, Ring Finger Protein; BRD, Bromodomain; CDK, Cyclin-dependent kinase; PAMPA, Parallel Artificial Membrane Permeability studies; BRET, Bioluminescence Resonance Energy Transfer; MCL, Mantle cell lymphoma; MCL-1, Myeloid Cell Leukemia 1; BCL-XL, B-cell lymphoma extra-large; TRK, Tropomyosin Receptor Kinase; RTKs, Transmembrane Receptor Tyrosine Kinase; NTRK, Neurotrophic Tyrosine Receptor Kinase; DHT, Dihydrotestosterone; EGFR, Epidermal Growth Factor Receptor; EGFR-TKIs, EGFR tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer; BCR, B-cell receptor; CML, Chronic myelogenous leukemia; TKI, Tyrosine kinase inhibitors; MoA, Mechanism of action; TPD, Targetted protein degraders; LYTACs, Lysosome targeting chimeras; ASGPR, Asialoglycoprotein receptor; AUTOTACs, Autophagy-Targeting Chimeras; ATTECs, Autophagy-tethering compounds; CRISPR-Cas9, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9; TALEN, Transcription Activator-Like Effector Nuclease; ZFN, Zinc Finger Nuclease.
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Affiliation(s)
- M Malarvannan
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal 700054, India
| | - Sujith Unnikrishnan
- Department of Pharmaceutical Analysis, Al Shifa College of Pharmacy, Perinthalmanna, Kerala 679325, India
| | - S Monohar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal 700054, India
| | - V Ravichandiran
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal 700054, India
| | - David Paul
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal 700054, India.
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Nair G, Saraswathy GR, Gayam PKR, Aranjani JM, Krishna Murthy TP, Subeesh V. Trailblazing real-world-data to confront hepatocellular carcinoma - disinterring repurposable drugs by amalgamating avant-garde stratagems. J Biomol Struct Dyn 2024:1-15. [PMID: 39687947 DOI: 10.1080/07391102.2024.2438361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 05/23/2024] [Indexed: 12/18/2024]
Abstract
Drug repurposing is preferred over de-novo drug discovery to unveil the therapeutic applications of existing drug candidates before investing considerable resources in unexplored novel chemical entities. This study demonstrated multifaceted stratagems to reconnoiter promising repurposable candidates against Hepatocellular Carcinoma (HCC) by amalgamating Real-World-Data (RWD) with bioinformatics algorithms corroborated with in-silico and in-vitro studies. At the outset, the RWD from the Food and Drug Administration Adverse Event Reporting System (FAERS) was explored to navigate signals to retrieve repurposable drugs that are inversely associated with HCC via Disproportionality Analysis. Further, transcriptomic analysis was used to capture the potential targets of HCC. Following this, the interactions between repurposable drugs and HCC targets were virtually demonstrated via molecular docking and Molecular Dynamics Simulations (MDS). Furthermore, additional cytotoxicity and gene expression experiments were conducted to corroborate the results. Overall, 64 drugs with Drug Event >5 were shortlisted as prospective repurposable drugs as per the RWD obtained from FAERS. The transcriptomic analysis highlighted significant upregulation of Cyclin A2 (CCNA2) in HCC, which activates Cyclin Dependent Kinase 2 (CDK2). Further, in-silico studies identified Losartan and Allopurinol, with docking scores of -7.11 and -6.219, respectively, as potential repurposable drugs. The selected drugs underwent further scrutiny through in-vitro studies. The treatment of HepG2 cells with Allopurinol resulted in significant downregulation of CCNA2/CDK2 expression with an elevation in reactive oxygen species levels, uncovering Allopurinol's anticancer mechanism through cellular apoptosis. This study suggests the importance of RWD in drug repurposing and the potential of Allopurinol as a repurposable drug against HCC.
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Affiliation(s)
- Gouri Nair
- Department of Pharmacology, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bangalore, Karnataka, India
| | - Ganesan Rajalekshmi Saraswathy
- Pharmacological Modelling and Simulation Centre, M. S. Ramaiah University of Applied Sciences, Bangalore, Karnataka, India
| | - Prasanna Kumar Reddy Gayam
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, India
| | - Jesil Mathew Aranjani
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, India
| | - T P Krishna Murthy
- Department of Biotechnology, M. S. Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - Viswam Subeesh
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, India
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Luo CH, Hu LH, Liu JY, Xia L, Zhou L, Sun RH, Lin CC, Qiu X, Jiang B, Yang MY, Zhang XH, Yang XB, Chen GQ, Lu Y. CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma. Nat Commun 2024; 15:10594. [PMID: 39632829 PMCID: PMC11618697 DOI: 10.1038/s41467-024-54354-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin lymphoma originating in the skin and invading the systemic hematopoietic system. Current treatments, including chemotherapy and monoclonal antibodies yielded limited responses with high incidence of side effects, highlighting the need for targeted therapy. Screening with small inhibitors library, herein we identify cyclin dependent kinase 9 (CDK9) as a driver of CTCL growth. Single-cell RNA-seq analysis reveals a CDK9high malignant T cell cluster with a unique actively proliferating feature. Inhibition, depletion or proteolysis targeting chimera (PROTAC)-mediated degradation of CDK9 significantly reduces CTCL cell growth in vitro and in murine models. CDK9 also promotes degradation of retinoic acid receptor α (RARα) via recruiting the E3 ligase HUWE1. Co-administration of CDK9-PROTAC (GT-02897) with all-trans retinoic acid (ATRA) leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL.
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MESH Headings
- Humans
- Animals
- Cyclin-Dependent Kinase 9/metabolism
- Cyclin-Dependent Kinase 9/antagonists & inhibitors
- Lymphoma, T-Cell, Cutaneous/metabolism
- Lymphoma, T-Cell, Cutaneous/drug therapy
- Lymphoma, T-Cell, Cutaneous/pathology
- Lymphoma, T-Cell, Cutaneous/genetics
- Mice
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/genetics
- Cell Line, Tumor
- Tumor Suppressor Proteins/metabolism
- Tumor Suppressor Proteins/genetics
- Retinoic Acid Receptor alpha/metabolism
- Retinoic Acid Receptor alpha/genetics
- Tretinoin/metabolism
- Tretinoin/pharmacology
- Xenograft Model Antitumor Assays
- Cell Proliferation/drug effects
- Skin Neoplasms/drug therapy
- Skin Neoplasms/metabolism
- Skin Neoplasms/pathology
- Skin Neoplasms/genetics
- Proteolysis/drug effects
- Female
- Mice, Inbred NOD
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Affiliation(s)
- Chen-Hui Luo
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li-Hong Hu
- Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie-Yang Liu
- Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Xia
- Department of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhou
- Department of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ren-Hong Sun
- Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai, China
| | - Chen-Cen Lin
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
| | - Xing Qiu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
| | - Biao Jiang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
| | - Meng-Ying Yang
- Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Xue-Hong Zhang
- Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
| | - Xiao-Bao Yang
- Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai, China.
| | - Guo-Qiang Chen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer, Research Units of Stress and Tumor (2019RU043), Chinese Academy of Medical Sciences, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
| | - Ying Lu
- Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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8
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Huang Y, Liu W, Zhao C, Shi X, Zhao Q, Jia J, Wang A. Targeting cyclin-dependent kinases: From pocket specificity to drug selectivity. Eur J Med Chem 2024; 275:116547. [PMID: 38852339 DOI: 10.1016/j.ejmech.2024.116547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/11/2024]
Abstract
The development of selective modulators of cyclin-dependent kinases (CDKs), a kinase family with numerous members and functional variations, is a significant preclinical challenge. Recent advancements in crystallography have revealed subtle differences in the highly conserved CDK pockets. Exploiting these differences has proven to be an effective strategy for achieving excellent drug selectivity. While previous reports briefly discussed the structural features that lead to selectivity in individual CDK members, attaining inhibitor selectivity requires consideration of not only the specific structures of the target CDK but also the features of off-target members. In this review, we summarize the structure-activity relationships (SARs) that influence selectivity in CDK drug development and analyze the pocket features that lead to selectivity using molecular-protein binding models. In addition, in recent years, novel CDK modulators have been developed, providing more avenues for achieving selectivity. These cases were also included. We hope that these efforts will assist in the development of novel CDK drugs.
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Affiliation(s)
- Yaoguang Huang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Wenwu Liu
- School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist., Beijing, 100084, People's Republic of China
| | - Changhao Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China
| | - Xiaoyu Shi
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Qingchun Zhao
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
| | - Jingming Jia
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
| | - Anhua Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
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Mulet-Lazaro R, Delwel R. Oncogenic Enhancers in Leukemia. Blood Cancer Discov 2024; 5:303-317. [PMID: 39093124 PMCID: PMC11369600 DOI: 10.1158/2643-3230.bcd-23-0211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/06/2024] [Accepted: 07/17/2024] [Indexed: 08/04/2024] Open
Abstract
Although the study of leukemogenesis has traditionally focused on protein-coding genes, the role of enhancer dysregulation is becoming increasingly recognized. The advent of high-throughput sequencing, together with a better understanding of enhancer biology, has revealed how various genetic and epigenetic lesions produce oncogenic enhancers that drive transformation. These aberrations include translocations that lead to enhancer hijacking, point mutations that modulate enhancer activity, and copy number alterations that modify enhancer dosage. In this review, we describe these mechanisms in the context of leukemia and discuss potential therapeutic avenues to target these regulatory elements. Significance: Large-scale sequencing projects have uncovered recurrent gene mutations in leukemia, but the picture remains incomplete: some patients harbor no such aberrations, whereas others carry only a few that are insufficient to bring about transformation on their own. One of the missing pieces is enhancer dysfunction, which only recently has emerged as a critical driver of leukemogenesis. Knowledge of the various mechanisms of enhancer dysregulation is thus key for a complete understanding of leukemia and its causes, as well as the development of targeted therapies in the era of precision medicine.
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Affiliation(s)
- Roger Mulet-Lazaro
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
- Oncode Institute, Utrecht, the Netherlands.
| | - Ruud Delwel
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
- Oncode Institute, Utrecht, the Netherlands.
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10
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Chen W, Wu Y, Yang C, Ren W, Hou L, Liang H, Wu T, Kong Y, Wu J, Rao Y, Chen C. CDK9 targeting PROTAC L055 inhibits ERα-positive breast cancer. Biomed Pharmacother 2024; 177:116972. [PMID: 38906024 DOI: 10.1016/j.biopha.2024.116972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/06/2024] [Accepted: 06/15/2024] [Indexed: 06/23/2024] Open
Abstract
Breast cancer is one of the most prevalent malignancies affecting women worldwide, underscoring the urgent need for more effective and specific treatments. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy to develop new lead compounds by selectively targeting oncoproteins for degradation. In this study, we designed, synthesized and evaluated a CRBN-based PROTAC, L055, which targets CDK9. Our findings demonstrate that L055 effectively inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells in vitro. L055 specifically binds to CDK9, facilitating its degradation via the CRBN-dependent proteasomal pathway. Additionally, L055 suppressed the growth of organoids and tumors derived from T47D and MCF7 cells in nude mice. Thus, L055 represents a potential novel therapeutic agent for ERα-positive breast cancer and potentially other malignancies.
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Affiliation(s)
- Wenmin Chen
- Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming 650204, China; Department of Basic Medical Sciences, Beihai Vocational College of Wellness, Beihai 536000, China
| | - Yue Wu
- MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China
| | - Chuanyu Yang
- Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Wenlong Ren
- Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; School of Life Science, University of Science & Technology of China, Hefei, Anhui 230027, China
| | - Lei Hou
- Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Huichun Liang
- Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Tingyue Wu
- Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; School of Life Science, University of Science & Technology of China, Hefei, Anhui 230027, China
| | - Yanjie Kong
- Pathology Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China.
| | - Jiao Wu
- Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China.
| | - Yu Rao
- MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China.
| | - Ceshi Chen
- Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China; The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China.
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11
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Sellars E, Savguira M, Wu J, Cancelliere S, Jen M, Krishnan R, Hakem A, Barsyte-Lovejoy D, Hakem R, Narod SA, Kotsopoulos J, Salmena L. A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity. iScience 2024; 27:110180. [PMID: 38993666 PMCID: PMC11238136 DOI: 10.1016/j.isci.2024.110180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 04/29/2024] [Accepted: 06/01/2024] [Indexed: 07/13/2024] Open
Abstract
PARP inhibitors (PARPi) are efficacious in BRCA1-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in BRCA1 wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.
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Affiliation(s)
- Erin Sellars
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
| | - Margarita Savguira
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jie Wu
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Sabrina Cancelliere
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Mark Jen
- Lunenfeld-Tanenbaum Research Institute, Network Biology Collaborative Centre, High-Throughput Screening, Mt. Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Rehna Krishnan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Anne Hakem
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Dalia Barsyte-Lovejoy
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Razqallah Hakem
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Steven A Narod
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Joanne Kotsopoulos
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Leonardo Salmena
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
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12
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Shaikh SA, Wakchaure SN, Labhade SR, Kale RR, Alavala RR, Chobe SS, Jain KS, Labhade HS, Bhanushali DD. Synthesis, biological evaluation, and molecular docking of novel 1,3,4-substituted-thiadiazole derivatives as potential anticancer agent. BMC Chem 2024; 18:119. [PMID: 38937800 PMCID: PMC11210122 DOI: 10.1186/s13065-024-01196-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 04/18/2024] [Indexed: 06/29/2024] Open
Abstract
In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides (4b-g), were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the hepatocellular carcinoma (HEPG-2), human lung carcinoma (A549), human breast carcinoma (MCF-7) and pseudo-normal human embryonic liver (L02) cancer cell lines by an MTT assay. Among all synthesized compounds, compound 8d showed the potent anti-cancer activities with GI50 values of 2.98, 2.85 and 2.53 μM against MCF-7, A549 and HepG-2 cell lines respectively as compared to standard drug Doxorubicin. Furthermore, molecular modelling studies have spotlighted the anchoring role of 1,3,4-substituted-thiadiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. Therefore, these results can provide promising starting points for further development of best anti-cancer agents.
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Affiliation(s)
- Samin A Shaikh
- Department of Chemistry, Savitribai Phule Pune University, Kr. V. N. Naik Shikshan Prasarak Sanstha's Arts, Commerce and Science College, Canada Corner, Nashik, Maharashtra, 422002, India.
- Department of Chemistry, Savitribai Phule Pune University, KTHM College, Nashik, Maharashtra, 422002, India.
| | - Satish N Wakchaure
- Department of Synthetic R & D, Delta Finochem Pvt. Ltd., G. No. 350, Wadivarhe, Igatpuri, Nashik, Maharashtra, 422403, India.
- Friedrich Alexander University Erlangen-Nuremberg (FAU), 91058, Erlangen, Germany.
| | - Shivaji R Labhade
- Department of Chemistry, Savitribai Phule Pune University, KTHM College, Nashik, Maharashtra, 422002, India
| | - Raju R Kale
- Department of Chemistry, Savitribai Phule Pune University, KTHM College, Nashik, Maharashtra, 422002, India
| | - Rajasekhar R Alavala
- SVKM's NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Vile Parle (W), Mumbai, Maharashtra, 400056, India
| | - Santosh S Chobe
- Department of Chemistry, Savitribai Phule Pune University, M.G.Vs. L. V. H. Arts, Science and Commerce College, Panchavati, Nashik, Maharashtra, 422003, India
| | - Kamlesh S Jain
- Department of Chemistry, Savitribai Phule Pune University, Kr. V. N. Naik Shikshan Prasarak Sanstha's Arts, Commerce and Science College, Canada Corner, Nashik, Maharashtra, 422002, India
| | - Hrishikesh S Labhade
- Department of Chemistry, Savitribai Phule Pune University, KTHM College, Nashik, Maharashtra, 422002, India
| | - Dipak D Bhanushali
- Department of Chemistry, Savitribai Phule Pune University, Kr. V. N. Naik Shikshan Prasarak Sanstha's Arts, Commerce and Science College, Canada Corner, Nashik, Maharashtra, 422002, India
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13
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Schmitt L, Hoppe J, Cea-Medina P, Bruch PM, Krings KS, Lechtenberg I, Drießen D, Peter C, Bhatia S, Dietrich S, Stork B, Fritz G, Gohlke H, Müller TJJ, Wesselborg S. Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs). Cell Death Discov 2024; 10:279. [PMID: 38862521 PMCID: PMC11167047 DOI: 10.1038/s41420-024-02056-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/31/2024] [Accepted: 06/03/2024] [Indexed: 06/13/2024] Open
Abstract
A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.
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Affiliation(s)
- Laura Schmitt
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Julia Hoppe
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Pablo Cea-Medina
- Institute for Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Peter-Martin Bruch
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Karina S Krings
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Ilka Lechtenberg
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Daniel Drießen
- Institute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Christoph Peter
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Sanil Bhatia
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Sascha Dietrich
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Björn Stork
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Gerhard Fritz
- Institute of Toxicology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Center (JSC) and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52425, Jülich, Germany
| | - Thomas J J Müller
- Institute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Sebastian Wesselborg
- Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Düsseldorf, Germany.
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14
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Patel DA, Patel SS, Patel HD. Advances in synthesis and biological evaluation of CDK2 inhibitors for cancer therapy. Bioorg Chem 2024; 143:107045. [PMID: 38147786 DOI: 10.1016/j.bioorg.2023.107045] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/27/2023] [Accepted: 12/15/2023] [Indexed: 12/28/2023]
Abstract
One of the leading causes of mortality in the world is cancer. This disease occurs when responsible genes that regulate the cell cycle become inactive due to internal or external factors. Specifically, the G1/S and S/G2 transitions in the cell cycle are controlled by a protein called cyclin-dependent kinase 2 (CDK2). CDKs, which play a crucial role in managing the cell cycle, have been a wide area of research in cancer treatment. Over the past 11 years, significant research has been made in identifying potent, targeted, and efficient inhibitors of CDK2. In this summary, we have summarized recent developments in the synthesis and biological evaluation of CDK2 inhibitors.
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Affiliation(s)
- Dharmesh A Patel
- Department of Chemistry, School of Sciences, Gujarat University, Navarangpura, Ahmedabad, Gujarat, India
| | - Siddharth S Patel
- Department of Chemistry, School of Sciences, Gujarat University, Navarangpura, Ahmedabad, Gujarat, India
| | - Hitesh D Patel
- Department of Chemistry, School of Sciences, Gujarat University, Navarangpura, Ahmedabad, Gujarat, India.
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15
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Kuo YH, Lai TC, Chang CH, Hsieh HC, Yang FM, Hu MC. 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) induces apoptosis in breast cancer cells through inhibiting of Mcl-1 expression. Sci Rep 2023; 13:12621. [PMID: 37537243 PMCID: PMC10400577 DOI: 10.1038/s41598-023-39340-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 07/24/2023] [Indexed: 08/05/2023] Open
Abstract
The effective treatment of breast cancer remains a profound clinical challenge, especially due to drug resistance and metastasis which unfortunately arise in many patients. The transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), as a selective inhibitor of cyclin-dependent kinase 9, was shown to be effective in inducing apoptosis in various hematopoietic malignancies. However, the anticancer efficacy of DRB against breast cancer is still unclear. Herein, we demonstrated that administration of DRB to the breast cancer cell line led to the inhibition of cellular proliferation and induction of the typical signs of apoptotic cells, including the increases in Annexin V-positive cells, DNA fragmentation, and activation of caspase-7, caspase-9, and poly (ADP ribose) polymerase (PARP). Treatment of DRB resulted in a rapid decline in the myeloid cell leukemia 1 (Mcl-1) protein, whereas levels of other antiapoptotic proteins did not change. Overexpression of Mcl-1 decreased the DRB-induced PARP cleavage, whereas knockdown of Mcl-1 enhanced the effects of DRB on PARP activation, indicating that loss of Mcl-1 accounts for the DRB-mediated apoptosis in MCF-7 cells, but not in T-47D. Furthermore, we found that co-treatment of MCF-7 cells with an inhibitor of AKT (LY294002) or an inhibitor of the proteasome (MG-132) significantly augmented the DRB-induced apoptosis. These data suggested that DRB in combination with LY294002 or MG-132 may have a greater therapeutic potency against breast cancer cells.
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Affiliation(s)
- Yi-Hsuan Kuo
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Tsai-Chun Lai
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
- Department of Life Sciences, College of Life Sciences, National Chung Hsing University, Taichung, 402, Taiwan
| | - Chia-Hsin Chang
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Han-Ching Hsieh
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Feng-Ming Yang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
| | - Meng-Chun Hu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan.
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16
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Alsfouk AA, Alshibl HM, Altwaijry NA, Alanazi A, AlKamaly O, Sultan A, Alsfouk BA. New Imadazopyrazines with CDK9 Inhibitory Activity as Anticancer and Antiviral: Synthesis, In Silico, and In Vitro Evaluation Approaches. Pharmaceuticals (Basel) 2023; 16:1018. [PMID: 37513929 PMCID: PMC10383573 DOI: 10.3390/ph16071018] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/11/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound 1d exhibited the highest CDK9 inhibition with an IC50 of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC50 values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound 4a showed the highest antiviral potency with an IC50 of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that 4a displayed a good affinity to proteases. The result of the docking studies of 4a with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents.
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Affiliation(s)
- Aisha A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Hanan M Alshibl
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Najla A Altwaijry
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Ashwag Alanazi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Omkulthom AlKamaly
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Ahlam Sultan
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Bshra A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
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17
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Quintela M, James DW, Garcia J, Edwards K, Margarit L, Das N, Lutchman-Singh K, Beynon AL, Rioja I, Prinjha RK, Harker NR, Gonzalez D, Steven Conlan R, Francis LW. In silico enhancer mining reveals SNS-032 and EHMT2 inhibitors as therapeutic candidates in high-grade serous ovarian cancer. Br J Cancer 2023; 129:163-174. [PMID: 37120667 PMCID: PMC10307814 DOI: 10.1038/s41416-023-02274-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 05/01/2023] Open
Abstract
BACKGROUND Epigenomic dysregulation has been linked to solid tumour malignancies, including ovarian cancers. Profiling of re-programmed enhancer locations associated with disease has the potential to improve stratification and thus therapeutic choices. Ovarian cancers are subdivided into histological subtypes that have significant molecular and clinical differences, with high-grade serous carcinoma representing the most common and aggressive subtype. METHODS We interrogated the enhancer landscape(s) of normal ovary and subtype-specific ovarian cancer states using publicly available data. With an initial focus on H3K27ac histone mark, we developed a computational pipeline to predict drug compound activity based on epigenomic stratification. Lastly, we substantiated our predictions in vitro using patient-derived clinical samples and cell lines. RESULTS Using our in silico approach, we highlighted recurrent and privative enhancer landscapes and identified the differential enrichment of a total of 164 transcription factors involved in 201 protein complexes across the subtypes. We pinpointed SNS-032 and EHMT2 inhibitors BIX-01294 and UNC0646 as therapeutic candidates in high-grade serous carcinoma, as well as probed the efficacy of specific inhibitors in vitro. CONCLUSION Here, we report the first attempt to exploit ovarian cancer epigenomic landscapes for drug discovery. This computational pipeline holds enormous potential for translating epigenomic profiling into therapeutic leads.
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Affiliation(s)
- Marcos Quintela
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - David W James
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Jetzabel Garcia
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Kadie Edwards
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Lavinia Margarit
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
- Cwm Taf Morgannwg University Health Board, Swansea, SA2 8QA, UK
| | - Nagindra Das
- Swansea Bay University Health Board, Swansea, SA12 7BR, UK
| | | | | | - Inmaculada Rioja
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, UK
| | - Rab K Prinjha
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, UK
| | - Nicola R Harker
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, UK
| | - Deyarina Gonzalez
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - R Steven Conlan
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Lewis W Francis
- Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK.
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18
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Zabihi M, Lotfi R, Yousefi AM, Bashash D. Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities. J Cancer Res Clin Oncol 2023; 149:1585-1606. [PMID: 35781526 DOI: 10.1007/s00432-022-04135-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/13/2022] [Indexed: 12/20/2022]
Abstract
The discussion on cell proliferation cannot be continued without taking a look at the cell cycle regulatory machinery. Cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) are valuable members of this system and their equilibrium guarantees the proper progression of the cell cycle. As expected, any dysregulation in the expression or function of these components can provide a platform for excessive cell proliferation leading to tumorigenesis. The high frequency of CDK abnormalities in human cancers, together with their druggable structure has raised the possibility that perhaps designing a series of inhibitors targeting CDKs might be advantageous for restricting the survival of tumor cells; however, their application has faced a serious concern, since these groups of serine-threonine kinases possess non-canonical functions as well. In the present review, we aimed to take a look at the biology of CDKs and then magnify their contribution to tumorigenesis. Then, by arguing the bright and dark aspects of CDK inhibition in the treatment of human cancers, we intend to reach a consensus on the application of these inhibitors in clinical settings.
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Affiliation(s)
- Mitra Zabihi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Lotfi
- Clinical Research Development Center, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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19
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Liu Y, Kong WY, Yu CF, Shao ZL, Lei QC, Deng YF, Cai GX, Zhuang XF, Sun WS, Wu SG, Wang R, Chen X, Chen GX, Huang HB, Liao YN. SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta Pharmacol Sin 2023; 44:853-864. [PMID: 36261513 PMCID: PMC10043269 DOI: 10.1038/s41401-022-01003-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/20/2022] [Indexed: 11/08/2022]
Abstract
Hepatocellular carcinoma (HCC) remains challenging due to the lack of efficient therapy. Promoting degradation of certain cancer drivers has become an innovative therapy. The nuclear transcription factor sine oculis homeobox 1 (SIX1) is a key driver for the progression of HCC. Here, we explored the molecular mechanisms of ubiquitination of SIX1 and whether targeting SIX1 degradation might represent a potential strategy for HCC therapy. Through detecting the ubiquitination level of SIX1 in clinical HCC tissues and analyzing TCGA and GEPIA databases, we found that ubiquitin specific peptidase 1 (USP1), a deubiquitinating enzyme, contributed to the lower ubiquitination and high protein level of SIX1 in HCC tissues. In HepG2 and Hep3B cells, activation of EGFR-AKT signaling pathway promoted the expression of USP1 and the stability of its substrates, including SIX1 and ribosomal protein S16 (RPS16). In contrast, suppression of EGFR with gefitinib or knockdown of USP1 restrained EGF-elevated levels of SIX1 and RPS16. We further revealed that SNS-023 (formerly known as BMS-387032) induced degradation of SIX1 and RPS16, whereas this process was reversed by reactivation of EGFR-AKT pathway or overexpression of USP1. Consequently, inactivation of the EGFR-AKT-USP1 axis with SNS-032 led to cell cycle arrest, apoptosis, and suppression of cell proliferation and migration in HCC. Moreover, we showed that sorafenib combined with SNS-032 or gefitinib synergistically inhibited the growth of Hep3B xenografts in vivo. Overall, we identify that both SIX1 and RPS16 are crucial substrates for the EGFR-AKT-USP1 axis-driven growth of HCC, suggesting a potential anti-HCC strategy from a novel perspective.
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Affiliation(s)
- Yuan Liu
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wei-Yao Kong
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Cui-Fu Yu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhen-Long Shao
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Qiu-Cheng Lei
- Department of Hepatopancreatic Surgery, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Yuan-Fei Deng
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Geng-Xi Cai
- Department of Breast Surgery, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Xue-Fen Zhuang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wen-Shuang Sun
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Shi-Gang Wu
- Department of Pathology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China
| | - Rong Wang
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China
| | - Xiang Chen
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China
| | - Guo-Xing Chen
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China.
| | - Hong-Biao Huang
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China.
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Yu-Ning Liao
- Department of General Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, China.
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
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20
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Wu X, Xie Y, Zhao K, Lu J. Targeting the super elongation complex for oncogenic transcription driven tumor malignancies: Progress in structure, mechanisms and small molecular inhibitor discovery. Adv Cancer Res 2023; 158:387-421. [PMID: 36990537 DOI: 10.1016/bs.acr.2022.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Oncogenic transcription activation is associated with tumor development and resistance derived from chemotherapy or target therapy. The super elongation complex (SEC) is an important complex regulating gene transcription and expression in metazoans closely related to physiological activities. In normal transcriptional regulation, SEC can trigger promoter escape, limit proteolytic degradation of transcription elongation factors and increase the synthesis of RNA polymerase II (POL II), and regulate many normal human genes to stimulate RNA elongation. Dysregulation of SEC accompanied by multiple transcription factors in cancer promotes rapid transcription of oncogenes and induce cancer development. In this review, we summarized recent progress in understanding the mechanisms of SEC in regulating normal transcription, and importantly its roles in cancer development. We also highlighted the discovery of SEC complex target related inhibitors and their potential applications in cancer treatment.
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Affiliation(s)
- Xinyu Wu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yanqiu Xie
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Kehao Zhao
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China.
| | - Jing Lu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China.
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21
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Mughal MJ, Bhadresha K, Kwok HF. CDK inhibitors from past to present: A new wave of cancer therapy. Semin Cancer Biol 2023; 88:106-122. [PMID: 36565895 DOI: 10.1016/j.semcancer.2022.12.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Deregulation of the cell cycle machinery, which has been linked to dysregulation of cyclin-dependent kinases (CDKs), is a defining characteristic of cancer, eventually promoting abnormal proliferation that feeds tumorigenesis and disease development. In this regard, several CDK inhibitors (CDKIs) have been developed during the last few decades (1st, 2nd, and 3rd generation CDKIs) to inhibit cancer cell proliferation. 1st and 2nd generation CDKIs have not received much clinical attention for the treatment of cancer patients because of their limited specificity and high toxicity. However, the recent development of combination strategies allowed us to reduce the toxicity and side effects of these CDKIs, paving the way for their potential application in clinical settings. The 3rd generation CDKIs have yielded the most promising results at the preclinical and clinical levels, propelling them into the advanced stages of clinical trials against multiple malignancies, especially breast cancer, and revolutionizing traditional treatment strategies. In this review, we discuss the most-investigated candidates from the 1st, 2nd, and 3rd generations of CDKIs, their basic mechanisms of action, the reasons for their failure in the past, and their current clinical development for the treatment of different malignancies. Additionally, we briefly highlighted the most recent clinical trial results and advances in the development of 3rd generation FDA-approved selective CDK4/6 inhibitors that combat the most prevalent cancer. Overall, this review will provide a thorough knowledge of CDKIs from the past to the present, allowing researchers to rethink and develop innovative cancer therapeutic regimens.
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Affiliation(s)
- Muhammad Jameel Mughal
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; MOE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States
| | - Kinjal Bhadresha
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; Hematology/Oncology Division, School of Medicine, Indiana University Indianapolis, IN, United States
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; MOE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR.
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22
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Aksoy O, Lind J, Sunder-Plaßmann V, Vallet S, Podar K. Bone marrow microenvironment- induced regulation of Bcl-2 family members in multiple myeloma (MM): Therapeutic implications. Cytokine 2023; 161:156062. [PMID: 36332463 DOI: 10.1016/j.cyto.2022.156062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/19/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022]
Abstract
In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today's most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.
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Affiliation(s)
- Osman Aksoy
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Judith Lind
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Vincent Sunder-Plaßmann
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Sonia Vallet
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria
| | - Klaus Podar
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria.
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23
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Li ZM, Liu G, Gao Y, Zhao MG. Targeting CDK7 in oncology: The avenue forward. Pharmacol Ther 2022; 240:108229. [PMID: 35700828 DOI: 10.1016/j.pharmthera.2022.108229] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/02/2022] [Accepted: 06/07/2022] [Indexed: 12/14/2022]
Abstract
Cyclin-dependent kinase (CDK) 7 is best characterized for the ability to regulate biological processes, including the cell cycle and gene transcription. Abnormal CDK7 activity is observed in various tumours and represents a driving force for tumourigenesis. Therefore, CDK7 may be an appealing target for cancer treatment. Whereas, the enthusiasm for CDK7-targeted therapeutic strategy is mitigated due to the widely possessed belief that this protein is essential for normal cells. Indeed, the fact confronts the consensus. This is the first review to introduce the role of CDK7 in pan-cancers via a combined analysis of comprehensive gene information and (pre)clinical research results. We also discuss the recent advances in protein structure and summarize the understanding of mechanisms underlying CDK7 function. These endeavours highlight the pivotal roles of CDK7 in tumours and may contribute to the development of effective CDK7 inhibitors within the strategy of structure-based drug discovery for cancer therapy.
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Affiliation(s)
- Zhi-Mei Li
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Guan Liu
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xinsi Road 1, Xi'an 710038, Shaanxi, PR China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, Henan, PR China.
| | - Ming-Gao Zhao
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China; Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xinsi Road 1, Xi'an 710038, Shaanxi, PR China.
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24
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Nature-Derived Compounds as Potential Bioactive Leads against CDK9-Induced Cancer: Computational and Network Pharmacology Approaches. Processes (Basel) 2022. [DOI: 10.3390/pr10122512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Given the importance of cyclin-dependent kinases (CDKs) in the maintenance of cell development, gene transcription, and other essential biological operations, CDK blockers have been generated to manage a variety of disorders resulting from CDK irregularities. Furthermore, CDK9 has a crucial role in transcription by regulating short-lived anti-apoptotic genes necessary for cancer cell persistence. Addressing CDK9 with blockers has consequently emerged as a promising treatment for cancer. This study scrutinizes the effectiveness of nature-derived compounds (geniposidic acid, quercetin, geniposide, curcumin, and withanolide C) against CDK9 through computational approaches. A molecular docking study was performed after preparing the protein and the ligands. The selected blockers of the CDK9 exerted reliable binding affinities (−8.114 kcal/mol to −13.908 kcal/mol) against the selected protein, resulting in promising candidates compared to the co-crystallized ligand (LCI). The binding affinity of geniposidic acid (−13.908 kcal/mol) to CDK9 is higher than quercetin (−10.775 kcal/mol), geniposide (−9.969 kcal/mol), curcumin (−9.898 kcal/mol), withanolide C (−8.114 kcal/mol), and the co-crystallized ligand LCI (−11.425 kcal/mol). Therefore, geniposidic acid is a promising inhibitor of CDK9. Moreover, the molecular dynamics studies assessed the structure–function relationships and protein–ligand interactions. The network pharmacology study for the selected ligands demonstrated the auspicious compound–target–pathway signaling pathways vital in developing tumor, tumor cell growth, differentiation, and promoting tumor cell progression. Moreover, this study concluded by analyzing the computational approaches the natural-derived compounds that have potential interacting activities against CDK9 and, therefore, can be considered promising candidates for CKD9-induced cancer. To substantiate this study’s outcomes, in vivo research is recommended.
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He XL, Hu YH, Chen JM, Zhang DQ, Yang HL, Zhang LZ, Mu YP, Zhang H, Chen GF, Liu W, Liu P. SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9. Front Pharmacol 2022; 13:1016552. [PMID: 36313366 PMCID: PMC9597511 DOI: 10.3389/fphar.2022.1016552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis is a common pathological process of all chronic liver diseases. Hepatic stellate cells (HSCs) play a central role in the development of liver fibrosis. Cyclin-dependent kinase 9 (CDK9) is a cell cycle kinase that regulates mRNA transcription and elongation. A CDK9 inhibitor SNS-032 has been reported to have good effects in anti-tumor. However, the role of SNS-032 in the development of liver fibrosis is unclear. In this study, SNS-032 was found to alleviate hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in carbon tetrachloride-induced model mice. In vitro, SNS-032 inhibited the activation and proliferation of active HSCs and induced the apoptosis of active HSCs by downregulating the expression of CDK9 and its downstream signal transductors, such phosphorylated RNA polymerase II and Bcl-2. CDK9 short hairpin RNA was transfected into active HSCs to further elucidate the mechanism of the above effects. Similar results were observed in active HSCs after CDK9 knockdown. In active HSCs with CDK9 knockdown, the expression levels of CDK9, phosphorylated RNA polymerase II, XIAP, Bcl-2, Mcl-1, and ɑ-SMA significantly decreased, whereas those of cleaved-PARP1 and Bax decreased prominently. These results indicated that SNS-032 is a potential drug and CDK9 might be a new prospective target for the treatment of liver fibrosis.
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Affiliation(s)
- Xiao-Li He
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Endocrinology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong-Hong Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jia-Mei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ding-Qi Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hai-Lin Yang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin-Zhang Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong-Ping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Gao-Feng Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Alsfouk AA, Alshibl HM, Alsfouk BA, Altwaijry NA, Al-Abdullah ES. Synthesis and Biological Evaluation of Imadazo[1,2-a]pyrazines as Anticancer and Antiviral Agents through Inhibition of CDK9 and Human Coronavirus. Pharmaceuticals (Basel) 2022; 15:ph15070859. [PMID: 35890157 PMCID: PMC9319549 DOI: 10.3390/ph15070859] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 02/04/2023] Open
Abstract
In this work, novel imadazo[1,2-a]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2-a]pyrazine 3c displayed the most potent CDK9 inhibitory activity with IC50 of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound 3c exhibited the most potent cytotoxicity effect with average IC50s of three cell lines of 6.66 µM. The drug likeness properties of 3c were predicated in silico and demonstrated that 3c have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2-a]pyrazine 3b exhibited the most potent anti-coronaviral activity with IC50 of 56.96 µM and selectivity index of 7.14. The target predication result revealed that 3b showed high affinity to protease enzyme. Docking studies of 3b with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data.
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Affiliation(s)
- Aisha A. Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia; (B.A.A.); (N.A.A.)
- Correspondence:
| | - Hanan M. Alshibl
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (H.M.A.); (E.S.A.-A.)
| | - Bshra A. Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia; (B.A.A.); (N.A.A.)
| | - Najla A. Altwaijry
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia; (B.A.A.); (N.A.A.)
| | - Ebtehal S. Al-Abdullah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (H.M.A.); (E.S.A.-A.)
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CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models. Cancers (Basel) 2022; 14:cancers14143361. [PMID: 35884422 PMCID: PMC9322647 DOI: 10.3390/cancers14143361] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/29/2022] [Accepted: 07/07/2022] [Indexed: 02/01/2023] Open
Abstract
Triple-negative breast cancers (TNBC) expressing PD-L1 qualify for checkpoint inhibitor immunotherapy. Cyclin E/CDK2 is a potential target axis in TNBC; however, small-molecule drugs at efficacious doses may be associated with toxicity, and treatment alongside immunotherapy requires investigation. We evaluated CDK inhibition at suboptimal levels and its anti-tumor and immunomodulatory effects. Transcriptomic analyses of primary breast cancers confirmed higher cyclin E/CDK2 expression in TNBC compared with non-TNBC. Out of the three CDK2-targeting inhibitors tested, the CDK 2, 7 and 9 inhibitor SNS-032 was the most potent in reducing TNBC cell viability and exerted cytotoxicity against all eight TNBC cell lines evaluated in vitro. Suboptimal SNS-032 dosing elevated cell surface PD-L1 expression in surviving TNBC cells. In mice engrafted with human immune cells and challenged with human MDA-MB-231 TNBC xenografts in mammary fat pads, suboptimal SNS-032 dosing partially restricted tumor growth, enhanced the tumor infiltration of human CD45+ immune cells and elevated cell surface PD-L1 expression in surviving cancer cells. In tumor-bearing mice engrafted with human immune cells, the anti-PD-L1 antibody avelumab, given sequentially following suboptimal SNS-032 dosing, reduced tumor growth compared with SNS-032 alone or with avelumab without prior SNS-032 priming. CDK inhibition at suboptimal doses promotes immune cell recruitment to tumors, PD-L1 expression by surviving TNBC cells and may complement immunotherapy.
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Abstract
Cyclin-dependent kinase (CDK) 9 associates mainly with cyclin T1 and forms the positive transcription elongation factor b (p-TEFb) complex responsible for transcriptional regulation. It has been shown that CDK9 modulates the expression and activity of oncogenes, such as MYC and murine double minute 4 (MDM4), and it also plays an important role in development and/or maintenance of the malignant cell phenotype. Malfunction of CDK9 is frequently observed in numerous cancers. Recent studies have highlighted the function of CDK9 through a variety of mechanisms in cancers, including the formation of new complexes and epigenetic alterations. Due to the importance of CDK9 activation in cancer cells, CDK9 inhibitors have emerged as promising candidates for cancer therapy. Natural product-derived and chemically synthesized CDK9 inhibitors are being examined in preclinical and clinical research. In this review, we summarize the current knowledge on the role of CDK9 in transcriptional regulation, epigenetic regulation, and different cellular factor interactions, focusing on new advances. We show the importance of CDK9 in mediating tumorigenesis and tumor progression. Then, we provide an overview of some CDK9 inhibitors supported by multiple oncologic preclinical and clinical investigations. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.
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29
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Yi X, Jain N, Iles LR, Ayres ML, Wierda WG, Gandhi V. Targeting Mcl-1 by AMG-176 During Ibrutinib and Venetoclax Therapy in Chronic Lymphocytic Leukemia. Front Oncol 2022; 12:833714. [PMID: 35273915 PMCID: PMC8901605 DOI: 10.3389/fonc.2022.833714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/12/2022] [Indexed: 11/13/2022] Open
Abstract
B-cell receptor (BCR) signaling pathway and Bcl-2 family prosurvival proteins, specifically Bcl-2 and Mcl-1, are functional in the pathobiology of chronic lymphocytic leukemia (CLL). A pivotal and apical molecule in the BCR pathway is Bruton’s tyrosine kinase (BTK). Together, BTK, Bcl-2, and Mcl-1 participate in the maintenance, migration, proliferation, and survival of CLL cells. Several ongoing and published clinical trials in CLL reported high rates of remission, namely, undetectable measurable residual disease (u-MRD) status with combined BTK inhibitor ibrutinib and Bcl-2 antagonist, venetoclax. While the majority of patients achieve complete remission with undetectable-measurable residual disease, at least one third of patients do not achieve this milestone. We hypothesized that cells persistent during ibrutinib and venetoclax therapy may be sensitive to combined venetoclax and Mcl-1 inhibitor, AMG-176. To test this hypothesis, we took peripheral blood samples at baseline, after Cycle 1 and Cycle 3 of ibrutinib monotherapy, after one week and 1 cycle of ibrutinib plus venetoclax therapy. These serial samples were tested for pharmacodynamic changes and treated in vitro with AMG-176 or in combination with venetoclax. Compared to C1D1 cells, residual cells during ibrutinib and venetoclax treatment were inherently resistant to endogenous cell death. Single agent exposure induced some apoptosis but combination of 100 nM venetoclax and 100 or 300 nM of AMG-176 resulted in 40–100% cell death in baseline samples. Cells obtained after four cycles of ibrutinib and one cycle of venetoclax, when treated with such concentration of venetoclax and AMG-176, showed 10–80% cell death. BCR signaling pathway, measured as autophosphorylation of BTK was inhibited throughout therapy in all post-therapy samples. Among four anti-apoptotic proteins, Mcl-1 and Bfl-1 decreased during therapy in most samples. Proapoptotic proteins decreased during therapy. Collectively, these data provide a rationale to test Mcl-1 antagonists alone or in combination in CLL during treatment with ibrutinib and venetoclax.
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Affiliation(s)
- Xue Yi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nitin Jain
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - LaKesla R Iles
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mary L Ayres
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - William G Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Varsha Gandhi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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30
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Xie Z, Hou S, Yang X, Duan Y, Han J, Wang Q, Liao C. Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts. J Med Chem 2022; 65:6356-6389. [PMID: 35235745 DOI: 10.1021/acs.jmedchem.1c02190] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inhibition of cyclin-dependent kinases (CDKs) has become an effective therapeutic strategy for treating various diseases, especially cancer. Over almost three decades, although great efforts have been made to discover CDK inhibitors, many of which have entered clinical trials, only four CDK inhibitors have been approved. In the process of CDK inhibitor development, many difficulties and misunderstandings have hampered their discovery and clinical applications, which mainly include inadequate understanding of the biological functions of CDKs, less attention paid to pan- and multi-CDK inhibitors, nonideal isoform selectivity of developed selective CDK inhibitors, overlooking the metabolic stability of early discovered CDK inhibitors, no effective resistance solutions, and a lack of available combination therapy and effective biomarkers for CDK therapies. After reviewing the mechanisms of CDKs and the research progress of CDK inhibitors, this perspective summarizes and discusses these difficulties or lessons, hoping to facilitate the successful discovery of more useful CDK inhibitors.
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Affiliation(s)
- Zhouling Xie
- Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China
| | - Shuzeng Hou
- Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China
| | - Xiaoxiao Yang
- Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China
| | - Yajun Duan
- Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China
| | - Jihong Han
- Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China
| | - Qin Wang
- Department of Otolaryngology─Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, P. R. China
| | - Chenzhong Liao
- Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China
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31
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Borowczak J, Szczerbowski K, Ahmadi N, Szylberg Ł. CDK9 inhibitors in multiple myeloma: a review of progress and perspectives. Med Oncol 2022; 39:39. [PMID: 35092513 PMCID: PMC8800928 DOI: 10.1007/s12032-021-01636-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/21/2021] [Indexed: 12/05/2022]
Abstract
Currently, multiple myeloma is not yet considered a curable disease. Despite the recent advances in therapy, the average patient lifespan is still unsatisfactory. Recently, CDK9 inhibitors emerged as a suitable agent to overcome resistance and prolong survival in patients with poor diagnoses. Downregulation of c-MYC, XIAP, Mcl-1 and restoration of p53 tumor-suppressive functions seems to play a key role in achieving clinical response. The applicability of the first generation of CDK9 inhibitors was limited due to relatively high toxicity, but the introduction of novel, highly selective drugs, seems to reduce the effects of off-target inhibition. CDK9 inhibitors were able to induce dose-dependent cytotoxicity in Doxorubicin-resistant, Lenalidomide-resistant and Bortezomib-resistant cell lines. They seem to be effective in cell lines with unfavorable prognostic factors, such as p53 deletion, t(4; 14) and t(14; 16). In preclinical trials, the application of CDK9 inhibitors led to tumor cells apoptosis, tumor growth inhibition and tumor mass reduction. Synergistic effects between CDK9 inhibitors and either Venetoclax, Bortezomib, Lenalidomide or Erlotinib have been proven and are awaiting verification in clinical trials. Although conclusions should be drawn with due care, obtained reports suggest that including CDK9 inhibitors into the current drug regimen may turn out to be beneficial, especially in poor prognosis patients.
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Affiliation(s)
- Jędrzej Borowczak
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
| | - Krzysztof Szczerbowski
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Navid Ahmadi
- Department of Cardiothoracic Surgery, Royal Papworth Hospital, Cambridge, UK
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
- Department of Tumor Pathology and Pathomorphology, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
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32
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El-Sayed AA, Nossier ES, Almehizia AA, Amr AEGE. Design, synthesis, anticancer evaluation and molecular docking study of novel 2,4-dichlorophenoxymethyl-based derivatives linked to nitrogenous heterocyclic ring systems as potential CDK-2 inhibitors. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.131285] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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33
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Alsfouk A. Small molecule inhibitors of cyclin-dependent kinase 9 for cancer therapy. J Enzyme Inhib Med Chem 2021; 36:693-706. [PMID: 33632038 PMCID: PMC7919902 DOI: 10.1080/14756366.2021.1890726] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 01/23/2023] Open
Abstract
Cyclin-dependent kinase 9 (CDK9) plays a vital role in transcription through regulation of short-lived anti-apoptotic genes required for cancer cell survival. Therefore, targeting CDK9 with small molecule inhibitors has emerged as a potential cancer therapy. This article reviews the most recent CDK9 patent literature (2012-2020) related to small molecule inhibitors in cancer along with their selectivity profile and biological results in preclinical studies.
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Affiliation(s)
- Aisha Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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34
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Zeng H, Yang H, Song Y, Fang D, Chen L, Zhao Z, Wang C, Xie S. Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma. Cell Death Dis 2021; 12:1048. [PMID: 34741018 PMCID: PMC8571299 DOI: 10.1038/s41419-021-04344-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 02/07/2023]
Abstract
Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.
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Affiliation(s)
- Huishan Zeng
- School of Pharmacy, Henan University, N. Jinming Avenue, 475004, Kaifeng, Henan, China
| | - Huiru Yang
- School of Pharmacy, Henan University, N. Jinming Avenue, 475004, Kaifeng, Henan, China
| | - Yifan Song
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Avenue, 475004, Kaifeng, China
| | - Dong Fang
- School of Pharmacy, Henan University, N. Jinming Avenue, 475004, Kaifeng, Henan, China
| | - Liang Chen
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Avenue, 475004, Kaifeng, China.
| | - Zhijun Zhao
- Department of Medicine and Therapeutics, Luohe Medical College, 462000, Luohe, China
| | - Chaojie Wang
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Avenue, 475004, Kaifeng, China.
| | - Songqiang Xie
- School of Pharmacy, Henan University, N. Jinming Avenue, 475004, Kaifeng, Henan, China.
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35
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Bhurta D, Bharate SB. Analyzing the scaffold diversity of cyclin-dependent kinase inhibitors and revisiting the clinical and preclinical pipeline. Med Res Rev 2021; 42:654-709. [PMID: 34605036 DOI: 10.1002/med.21856] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 07/04/2021] [Accepted: 09/21/2021] [Indexed: 12/17/2022]
Abstract
Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin-dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino-pyrimidine is a well-represented scaffold. The three-nitrogen framework of amino-pyrimidine is a fundamental hinge-binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose-limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP-binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.
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Affiliation(s)
- Deendyal Bhurta
- Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Sandip B Bharate
- Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
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36
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Faber EB, Wang N, Georg GI. Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†. Biol Reprod 2021; 103:357-367. [PMID: 32543655 PMCID: PMC7523694 DOI: 10.1093/biolre/ioaa107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/03/2020] [Accepted: 04/19/2020] [Indexed: 12/30/2022] Open
Abstract
Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.
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Affiliation(s)
- Erik B Faber
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota-Twin Cities, Minneapolis, MN, USA.,Medical-Scientist Training Program, University of Minnesota Medical School, University of Minnesota-Twin Cities, Minneapolis, MN, USA
| | - Nan Wang
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota-Twin Cities, Minneapolis, MN, USA
| | - Gunda I Georg
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota-Twin Cities, Minneapolis, MN, USA
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Kwok M, Agathanggelou A, Davies N, Stankovic T. Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives. Cancers (Basel) 2021; 13:4681. [PMID: 34572908 PMCID: PMC8468925 DOI: 10.3390/cancers13184681] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/16/2021] [Accepted: 09/16/2021] [Indexed: 12/20/2022] Open
Abstract
The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the 'undruggable' p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL.
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Affiliation(s)
- Marwan Kwok
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2SY, UK; (A.A.); (N.D.)
- Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham B15 2SY, UK
| | - Angelo Agathanggelou
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2SY, UK; (A.A.); (N.D.)
| | - Nicholas Davies
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2SY, UK; (A.A.); (N.D.)
| | - Tatjana Stankovic
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2SY, UK; (A.A.); (N.D.)
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Inhibitors Targeting CDK9 Show High Efficacy against Osimertinib and AMG510 Resistant Lung Adenocarcinoma Cells. Cancers (Basel) 2021; 13:cancers13153906. [PMID: 34359807 PMCID: PMC8345430 DOI: 10.3390/cancers13153906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Non-small cell lung cancer accounts for 80% of all lung cancer cases. While a subset of non-small cell lung cancer patients respond to immunotherapy, those who are treated with chemotherapy or targeted therapy develop resistance to the drugs. Thus, novel therapeutic strategies are needed to combat this disease. Here we show that inhibitors of the cyclin-dependent kinase 9 are highly effective in preventing the growth of a variety of lung cancer cell lines and lung cancer organoids with high potency. These inhibitors suppressed the expression of several genes like Sox2, Sox9, and Mcl1 that promote tumor growth, facilitating growth arrest. Since inhibitors of cyclin-dependent kinase 9 are undergoing clinical trials for hematological malignancies, our studies suggest that these inhibitors would be attractive candidates to combat non-small cell lung cancer. Abstract Non-small cell lung cancer has a 5-year survival rate of less than 12–15%, calling for the development of additional therapeutic strategies to combat this disease. Here we tested the efficacy of inhibiting cyclin-dependent kinase 9 (CDK9) on lung cancer cell lines with K-Ras and EGFR mutations and on lung cancer organoids. Three different CDK9 inhibitors reduced the viability and anchorage-independent growth of lung cancer cell lines at very low nanomolar to micromolar concentrations. CDK9 inhibition suppressed the expression of the anti-apoptotic protein, Mcl1, as well as the embryonic stem cell transcription factors, Sox2 and Sox9, which are pro-tumorigenic. In contrast, treatment with CDK9 inhibitors increased the levels of WT p53 and its downstream target p21 in K-Ras mutant cell lines. Furthermore, the CDK9 inhibitors could markedly reduce the viability of Osimertinib-resistant PC9 and AMG510-resistant H23 and H358 cells with comparable efficacy as the parental cells. CDK9 inhibitors could also significantly reduce the growth and viability of lung cancer organoids with high potency. Taken together, the data presented here strongly suggest that CDK9 inhibitors would be efficacious against K-Ras mutant and EGFR mutant NSCLCs, including those that develop resistance to targeted therapies.
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Susanti NMP, Tjahjono DH. Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment. Molecules 2021; 26:molecules26154462. [PMID: 34361615 PMCID: PMC8348313 DOI: 10.3390/molecules26154462] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 12/24/2022] Open
Abstract
In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy’s effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.
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Affiliation(s)
- Ni Made Pitri Susanti
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia;
- Study Program of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Udaya, Jalan Bukit Jimbaran, Badung 80361, Indonesia
| | - Daryono Hadi Tjahjono
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia;
- Correspondence: ; Tel.: +62-812-2240-0120
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40
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Yu F, Cai M, Shao L, Zhang J. Targeting Protein Kinases Degradation by PROTACs. Front Chem 2021; 9:679120. [PMID: 34277564 PMCID: PMC8279777 DOI: 10.3389/fchem.2021.679120] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/15/2021] [Indexed: 12/30/2022] Open
Abstract
Kinase dysregulation is greatly associated with cell proliferation, migration and survival, indicating the importance of kinases as therapeutic targets for anticancer drug development. However, traditional kinase inhibitors binding to catalytic or allosteric sites are associated with significant challenges. The emergence of resistance and targeting difficult-to-degrade and multi-domain proteins are significant limiting factors affecting the efficacy of targeted anticancer drugs. The next-generation treatment approaches seem to have overcome these concerns, and the use of proteolysis targeting chimera (PROTAC) technology is one such method. PROTACs bind to proteins of interest and recruit E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway. This review provides a detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry.
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Affiliation(s)
- Fei Yu
- Medical School of Kunming University of Science and Technology, Kunming, China
| | - Ming Cai
- Medical School of Kunming University of Science and Technology, Kunming, China
| | - Liang Shao
- Medical School of Kunming University of Science and Technology, Kunming, China
| | - Jihong Zhang
- Medical School of Kunming University of Science and Technology, Kunming, China
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41
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Ketley A, Wojciechowska M, Ghidelli-Disse S, Bamborough P, Ghosh TK, Morato ML, Sedehizadeh S, Malik NA, Tang Z, Powalowska P, Tanner M, Billeter-Clark R, Trueman RC, Geiszler PC, Agostini A, Othman O, Bösche M, Bantscheff M, Rüdiger M, Mossakowska DE, Drewry DH, Zuercher WJ, Thornton CA, Drewes G, Uings I, Hayes CJ, Brook JD. CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model. Sci Transl Med 2021; 12:12/541/eaaz2415. [PMID: 32350131 DOI: 10.1126/scitranslmed.aaz2415] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/16/2019] [Accepted: 02/25/2020] [Indexed: 12/17/2022]
Abstract
Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSALR mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.
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Affiliation(s)
- Ami Ketley
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Marzena Wojciechowska
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Sonja Ghidelli-Disse
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 61997 Heidelberg, Germany
| | - Paul Bamborough
- Computational and Modelling Sciences, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK
| | - Tushar K Ghosh
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Marta Lopez Morato
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Saam Sedehizadeh
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Naveed Altaf Malik
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Zhenzhi Tang
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642-0001, USA
| | - Paulina Powalowska
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.,School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
| | - Matthew Tanner
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642-0001, USA
| | - Rudolf Billeter-Clark
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Rebecca C Trueman
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Philippine C Geiszler
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Alessandra Agostini
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Othman Othman
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Markus Bösche
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 61997 Heidelberg, Germany
| | - Marcus Bantscheff
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 61997 Heidelberg, Germany
| | - Martin Rüdiger
- Screening Profiling and Mechanistic Biology, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK
| | - Danuta E Mossakowska
- Discovery Partnerships with Academia, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK.,Malopolska Centre of Biotechnology, Jagiellonian University, 30-348 Krakow, Poland
| | - David H Drewry
- Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA
| | - William J Zuercher
- Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA.,SGC Center for Chemical Biology, UNC, Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA
| | - Charles A Thornton
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642-0001, USA
| | - Gerard Drewes
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 61997 Heidelberg, Germany
| | - Iain Uings
- Discovery Partnerships with Academia, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK
| | - Christopher J Hayes
- School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
| | - J David Brook
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
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Mandal R, Becker S, Strebhardt K. Targeting CDK9 for Anti-Cancer Therapeutics. Cancers (Basel) 2021; 13:2181. [PMID: 34062779 PMCID: PMC8124690 DOI: 10.3390/cancers13092181] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/23/2022] Open
Abstract
Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner-Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.
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Affiliation(s)
- Ranadip Mandal
- Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (R.M.); (S.B.)
| | - Sven Becker
- Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (R.M.); (S.B.)
| | - Klaus Strebhardt
- Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (R.M.); (S.B.)
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Kazi A, Chen L, Xiang S, Vangipurapu R, Yang H, Beato F, Fang B, Williams TM, Husain K, Underwood P, Fleming JB, Malafa M, Welsh EA, Koomen J, Trevino J, Sebti SM. Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer. Clin Cancer Res 2021; 27:4012-4024. [PMID: 33879459 DOI: 10.1158/1078-0432.ccr-20-4781] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/27/2021] [Accepted: 04/16/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Among human cancers that harbor mutant (mt) KRas, some, but not all, are dependent on mt KRas. However, little is known about what drives KRas dependency. EXPERIMENTAL DESIGN Global phosphoproteomics, screening of a chemical library of FDA drugs, and genome-wide CRISPR/Cas9 viability database analysis were used to identify vulnerabilities of KRas dependency. RESULTS Global phosphoproteomics revealed that KRas dependency is driven by a cyclin-dependent kinase (CDK) network. CRISPR/Cas9 viability database analysis revealed that, in mt KRas-driven pancreatic cancer cells, knocking out the cell-cycle regulators CDK1 or CDK2 or the transcriptional regulators CDK7 or CDK9 was as effective as knocking out KRas. Furthermore, screening of a library of FDA drugs identified AT7519, a CDK1, 2, 7, and 9 inhibitor, as a potent inducer of apoptosis in mt KRas-dependent, but not in mt KRas-independent, human cancer cells. In vivo AT7519 inhibited the phosphorylation of CDK1, 2, 7, and 9 substrates and suppressed growth of xenografts from 5 patients with pancreatic cancer. AT7519 also abrogated mt KRas and mt p53 primary and metastatic pancreatic cancer in three-dimensional (3D) organoids from 2 patients, 3D cocultures from 8 patients, and mouse 3D organoids from pancreatic intraepithelial neoplasia, primary, and metastatic tumors. CONCLUSIONS A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in patients with pancreatic cancer.
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Affiliation(s)
- Aslamuzzaman Kazi
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Liwei Chen
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Shengyan Xiang
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Rajanikanth Vangipurapu
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Hua Yang
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Francisca Beato
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Bin Fang
- Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Terence M Williams
- Department of Radiation Oncology, The Ohio State University, Columbus, Ohio
| | - Kazim Husain
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | | | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Mokenge Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Eric A Welsh
- Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - John Koomen
- Molecular Oncology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - José Trevino
- Department of Surgery, University of Florida, Gainesville, Florida
| | - Saïd M Sebti
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. .,Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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Chen R, Tsai J, Thompson PA, Chen Y, Xiong P, Liu C, Burrows F, Sivina M, Burger JA, Keating MJ, Wierda WG, Plunkett W. The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action. Blood Cancer J 2021; 11:57. [PMID: 33714981 PMCID: PMC7956145 DOI: 10.1038/s41408-021-00436-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/13/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023] Open
Abstract
The constitutive activation of B-cell receptor (BCR) signaling, together with the overexpression of the Bcl-2 family anti-apoptotic proteins, represents two hallmarks of chronic lymphocytic leukemia (CLL) that drive leukemia cell proliferation and sustain their survival. TG02 is a small molecule multi-kinase inhibitor that simultaneously targets both of these facets of CLL pathogenesis. First, its inhibition of cyclin-dependent kinase 9 blocked the activation of RNA polymerase II and transcription. This led to the depletion of Mcl-1 and rapid induction of apoptosis in the primary CLL cells. This mechanism of apoptosis was independent of CLL prognostic factors or prior treatment history, but dependent on the expression of BAX and BAK. Second, TG02, which inhibits the members of the BCR signaling pathway such as Lck and Fyn, blocked BCR-crosslinking-induced activation of NF-κB and Akt, indicating abrogation of BCR signaling. Finally, the combination of TG02 and ibrutinib demonstrated moderate synergy, suggesting a future combination of TG02 with ibrutinib, or use in patients that are refractory to the BCR antagonists. Thus, the dual inhibitory activity on both the CLL survival pathway and BCR signaling identifies TG02 as a unique compound for clinical development in CLL and possibly other B cell malignancies.
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Affiliation(s)
- Rong Chen
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
| | - Jennifer Tsai
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.,Department of Emergency Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Philip A Thompson
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Yuling Chen
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Ping Xiong
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Chaomei Liu
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Francis Burrows
- Tragara Pharmaceuticals, Carlsbad, CA, USA.,Kura Oncology, Inc., San Diego, CA, USA
| | - Mariela Sivina
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jan A Burger
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Michael J Keating
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - William G Wierda
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - William Plunkett
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.,Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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Huang WL, Abudureheman T, Xia J, Chu L, Zhou H, Zheng WW, Zhou N, Shi RY, Li MH, Zhu JM, Qing K, Ji C, Liang KW, Guo S, Yin G, Duan CW. CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism. Front Cell Dev Biol 2021; 9:641271. [PMID: 33748130 PMCID: PMC7969802 DOI: 10.3389/fcell.2021.641271] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/10/2021] [Indexed: 12/18/2022] Open
Abstract
B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.
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Affiliation(s)
- Wen-Li Huang
- Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China.,Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Tuersunayi Abudureheman
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xia
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Chu
- Department of Gynecology and Obstetrics, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hang Zhou
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Collaborative Innovation Center for Translational Medicine, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-Wei Zheng
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Neng Zhou
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong-Yi Shi
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Hao Li
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Min Zhu
- Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Qing
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Ji
- Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Kai-Wei Liang
- Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Sa Guo
- Department of Gynecology and Obstetrics, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gang Yin
- Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China
| | - Cai-Wen Duan
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.,Key Laboratory of Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Collaborative Innovation Center for Translational Medicine, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ma H, Dean DC, Wei R, Hornicek FJ, Duan Z. Cyclin-dependent kinase 7 (CDK7) is an emerging prognostic biomarker and therapeutic target in osteosarcoma. Ther Adv Musculoskelet Dis 2021; 13:1759720X21995069. [PMID: 34104229 PMCID: PMC8164556 DOI: 10.1177/1759720x21995069] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/10/2020] [Indexed: 11/17/2022] Open
Abstract
Background: Overexpression of cyclin-dependent kinase 7 (CDK7) is a well-known pathogenic feature of various malignancies and a sign of a more dismal prognosis. As relatively little is known about CDK7 in osteosarcoma, we elected to evaluate its expression, prognostic value, and function. Methods: We began by analyzing the publicly available data sets on CDK7 expression, including RNA sequencing data from the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) and the Gene Expression database of Normal and Tumor tissues 2 (GENT2). The correlation between patient tissue CDK7 expression and their clinicopathological features and prognosis was assessed via immunohistochemical staining of a unique tissue microarray constructed from osteosarcoma specimens. Furthermore, we analyzed CDK7 expression in osteosarcoma cell lines and tissues by Western blot. CDK7-specific siRNA and a highly-selective CDK7 inhibitor, BS-181, were applied to determine the function of CDK7 on osteosarcoma cell growth and proliferation. In addition, the effect of CDK7 inhibition on clonogenicity was evaluated using a clonogenic assay, and a 3D cell culture model was used to mimic CDK7 effects in an in vivo environment. Results: Our results demonstrate that higher CDK7 expression significantly correlates with recurrence, metastasis, and shorter overall survival in osteosarcoma patients. Therapeutically, we show that CDK7 knockdown with siRNA or selective inhibition with BS-181 decreases proliferation and induces apoptosis of osteosarcoma cells. Conclusion: This study supports CDK7 overexpression as an independent predictor of poor prognosis and promising therapeutic target for osteosarcoma.
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Affiliation(s)
- Hangzhan Ma
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Dylan C Dean
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ran Wei
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Francis J Hornicek
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Zhenfeng Duan
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Los Angeles, CA 90095, USA
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Qiu X, Li Y, Yu B, Ren J, Huang H, Wang M, Ding H, Li Z, Wang J, Bian J. Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion. Eur J Med Chem 2021; 211:113091. [PMID: 33338869 DOI: 10.1016/j.ejmech.2020.113091] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/05/2020] [Accepted: 12/05/2020] [Indexed: 10/22/2022]
Abstract
Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. In addition, the most potent PROTAC molecule B03 could inhibit cell growth more effectively than warhead alone, with little inhibition of other kinases. This enhanced antiproliferative activity is mediated by a slight increase in kinase inhibitory activity and an increase in the level of apoptosis induction. Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia.
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Affiliation(s)
- Xiaqiu Qiu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuanqing Li
- State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Bin Yu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jie Ren
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Huidan Huang
- School of Pharmacy, Wannan Medical College, Wuhu, 241002, PR China.
| | - Min Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hong Ding
- State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Zhiyu Li
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jubo Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jinlei Bian
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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Abstract
Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.
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49
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Synthesis and biological evaluation of seliciclib derivatives as potent and selective CDK9 inhibitors for prostate cancer therapy. MONATSHEFTE FUR CHEMIE 2021. [DOI: 10.1007/s00706-020-02727-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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50
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Synthesis, characterization and in-silico assessment of novel thiazolidinone derivatives for cyclin-dependent kinases-2 inhibitors. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2020.129311] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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