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Ibrahim S, Khan MU, Khurram I, Ghani MU, Sharifi-Rad J, Calina D. Anticancer efficacy of Spiruchostatin A: current insights into histone deacetylase inhibition and oncologic applications. Eur J Med Res 2025; 30:169. [PMID: 40082963 PMCID: PMC11907871 DOI: 10.1186/s40001-025-02401-0] [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: 05/21/2024] [Accepted: 02/21/2025] [Indexed: 03/16/2025] Open
Abstract
Spiruchostatin A also referred to as YM753 and OBP801, a cyclic peptide-based natural product derived from Pseudomonas sp., is distinguished by its potent inhibition of Class I histone deacetylases (HDACs). The modulation of epigenetic mechanisms by HDAC inhibitors is fundamental for altering gene expression related to cell growth, apoptosis, and differentiation, highlighting their potential in oncologic therapies. This updated review assesses the antitumor efficacy of Spiruchostatin A across diverse cellular and animal models, scrutinizing its viability as a therapeutic agent against various cancers. A systematic literature review was executed by searching databases such as PubMed/MedLine, Scopus, and Web of Science from October 2022 to February 2023. The inclusion criteria focused on studies involving Spiruchostatin A in the context of cancer treatment, including in vitro and in vivo models. The review concentrated on the compound's mechanistic action, biological activity, and clinical applicability. Spiruchostatin A has demonstrated significant antitumor activities, including inducing apoptosis and inhibiting tumor growth effectively in multiple models. Its therapeutic potential is particularly noted in synergistic applications with other anticancer agents, enhancing its efficacy. Mechanistically, the compound facilitates chromatin relaxation and transcriptional activation of key tumor suppressor genes through increased histone acetylation. Spiruchostatin A exhibits substantial potential as an anticancer agent through effective HDAC inhibition and subsequent epigenetic modifications of cancer cell biology. However, comprehensive clinical trials are imperative to validate its efficacy and safety profiles comprehensively. Future research is warranted to elucidate detailed molecular mechanisms and to develop biomarkers for predicting treatment response. Comprehensive longitudinal clinical studies are also critical to establish Spiruchostatin A's role within the broader oncological therapeutic regimen, along with the exploration of its analogs for improved therapeutic outcomes.
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Affiliation(s)
- Saooda Ibrahim
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Umer Khan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
| | - Iqra Khurram
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Usman Ghani
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, Ecuador.
- Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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2
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Peng R, Zhan Y, Li A, Lv Q, Xu S. Research progress and development strategy of PI3K inhibitors for breast cancer treatment: A review (2016-present). Bioorg Chem 2024; 153:107934. [PMID: 39509786 DOI: 10.1016/j.bioorg.2024.107934] [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: 09/05/2024] [Revised: 10/21/2024] [Accepted: 10/27/2024] [Indexed: 11/15/2024]
Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are widely expressed in tissues and cells throughout the body and are involved in a variety of physiological processes including cell growth and metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR, PAM) is a promising target for the treatment of many cancer types because it is significantly linked to tumorigenesis and development. Aberrant activation of this pathway is observed in the majority of tumors, particularly in breast cancer. The development of PI3K inhibitors has received much attention in recent years. PI3K inhibitors are effective drugs for the treatment of various types of malignant tumors. The FDA has approved a few PI3K inhibitors for commercialization, and the majority of PI3K inhibitors under clinical trials are expected to conquer cancers, including breast cancer. This article discusses the link between the PAM signaling system and breast cancer, as well as the current clinical applications of PAM pathway inhibitors in the treatment of breast cancer. This work summarizes and describes the development tactics of seven types of PI3K inhibitors targeting breast cancer, including morpholine-substituted thienopyrimidines, with the goal of informing future PI3K inhibitor research.
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Affiliation(s)
- Rujue Peng
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China
| | - Yujie Zhan
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China
| | - Anqi Li
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China
| | - Qiaoli Lv
- Department of Oncology, Jiangxi Cancer Hospital, Nanchang 330029, China.
| | - Shan Xu
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
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3
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Lin Y, Itoh H, Dan S, Inoue M. Methyl scanning approach for enhancing the biological activity of the linear peptidic natural product, efrapeptin C. Chem Sci 2024; 15:19390-19399. [PMID: 39568880 PMCID: PMC11575625 DOI: 10.1039/d4sc04384g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/15/2024] [Indexed: 11/22/2024] Open
Abstract
Efrapeptin C (1a) is a large peptidic natural product comprising a 15-mer linear sequence and exerts potent anticancer activity by inhibiting mitochondrial FoF1-ATP synthase. Residues 1-6 and 9-15 of 1a fold into two 310-helical domains and interact with ATP synthase, while the central β-Ala-7-Gly-8 region functions as a flexible linker of the two domains. To enhance the function of 1a by minimally modifying its structure, we envisioned attaching one small methyl group to the β-Ala-7-Gly-8 and designed six methylated analogues 1b-1g, differing only in the position and configuration of the methyl group. We enabled the first solid-phase total synthesis of 1a and unified syntheses of 1b-1g. The growth inhibitory activities of 1a-1g against MCF-7 cells varied significantly: 1f with (S)-β3-hAla-7 and its epimer 1g with (R)-β3-hAla-7 were 4-fold more and 5-fold less potent, respectively, than 1a. Remarkably, the most potent 1f had the most stabilized 310-helical conformation and the highest hydrophobicity, which likely contributed to its effective transfer to the target protein within mitochondria. Moreover, 1f exhibited higher proteolytic stability than 1a. Therefore, the present methyl scanning approach provides a new strategy for changing the original properties of linear peptidic natural products to develop new pharmaceuticals.
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Affiliation(s)
- Yuanqi Lin
- Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan
| | - Hiroaki Itoh
- Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research 3-8-31 Ariake Koto-ku Tokyo 135-8550 Japan
| | - Masayuki Inoue
- Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan
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Li M, Liu J, Jin L, Mi T, Zhang Z, Zhanghuang C, Li M, Wang J, Wu X, Wang Z, Wang Z, He D. ZSTK474 targeting PIK3R3 inhibits the Wilms' tumor through G0 / G1 phase arrest. PLoS One 2024; 19:e0312178. [PMID: 39466763 PMCID: PMC11515993 DOI: 10.1371/journal.pone.0312178] [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: 07/05/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024] Open
Abstract
PURPOSE Wilms' tumor (WT), also known as nephroblastoma, is the predominant form of primary malignant renal cancer. The unfavorable prognoses linked to anaplastic nephroblastoma and recurrent nephroblastoma emphasize the crucial requirement for the exploration of innovative treatment modalities for WT. METHODS Our study conducted one-way Cox regression and Kaplan-Meier analyses using TARGET-WT nephroblastoma data to identify differentially expressed genes in nephroblastoma and evaluate their prognostic relevance. Utilizing the Connectivity Map database, ZSTK474 emerged as a viable therapeutic option for WT. The effect of ZSTK474 on WT and related underlying mechanisms were further investigated through in vitro and in vivo investigations. RESULTS The in vivo experiment results indicated that ZSTK474 effectively inhibited subcutaneous tumor growth in WT mice. CCK-8 assays revealed two nephroblastoma cell lines exhibited half-inhibitory concentrations of 2μM and 2.51μM for ZSTK474, respectively. ZSTK474 was shown to inhibit the migration and invasion capabilities of WT cells in both Transwell and wound healing assays. Flow cytometry apoptosis and TUNEL assays demonstrated that ZSTK474 induced apoptosis in WT cells. Cell cycle analysis revealed that ZSTK474 led to the induction of G0/G1 phase arrest. Sequencing of ZSTK474-treated WiT49 cells suggested that the impact of ZSTK474 on WT might be mediated by the PI3K/Akt pathway, specifically by inhibiting PIK3R3. Knock-down of PIK3R3 confirmed that ZSTK474 downregulated PIK3R3, reducing Akt phosphorylation, cyclin D and CDK4 levels and elevating P21 expression in nephroblastoma cells. However, current research has limitations, including a lack of understanding of the long-term effects and potential resistance mechanisms of new therapies. CONCLUSION This research provides insight into the potential of ZSTK474 and other PI3K inhibitors for treating nephroblastoma.
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Affiliation(s)
- Maoxian Li
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
- Department of Pediatric Surgery, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Jiayan Liu
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Liming Jin
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Tao Mi
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Zhaoxia Zhang
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Chenghao Zhanghuang
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Mujie Li
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Jinkui Wang
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Xin Wu
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Zhaoying Wang
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Zhang Wang
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
| | - Dawei He
- Department of Urology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, P.R China
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Lim HY, Dolzhenko AV. 1,3,5-Triazine as a promising scaffold in the development of therapeutic agents against breast cancer. Eur J Med Chem 2024; 276:116680. [PMID: 39018924 DOI: 10.1016/j.ejmech.2024.116680] [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: 05/02/2024] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024]
Abstract
1,3,5-Triazine scaffold has garnered considerable interest due to its wide-ranging pharmacological properties, particularly in the field of cancer research. Breast cancer is the most commonly diagnosed cancer among women. Approximately one in eight women will receive a diagnosis of invasive breast cancer during their lifetime. The five-year survival rate for invasive breast cancer is less than 30 %, indicating a need to develop a more effective therapeutic agent targeting breast cancer. This review discusses bioactive 1,3,5-triazines targeting breast cancer cells by the inhibition of different enzymes, which include PI3K, mTOR, EGFR, VEGFR, FAK, CDK, DHFR, DNA topoisomerase, ubiquitin-conjugating enzyme, carbonic anhydrase, and matrix metalloproteinase. The anticancer agent search in some drug discovery programs is based on compound screening for antiproliferative activity. Often, multiple targets contribute to the anticancer effect of 1,3,5-triazines and this approach allows identification of active molecules prior to identification of their targets.
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Affiliation(s)
- Han Yin Lim
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia.
| | - Anton V Dolzhenko
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; Curtin Medical School, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987 Perth, Western, Bentley, 6845, Australia
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6
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Dehghani-Ghahnaviyeh S, Soylu C, Furet P, Velez-Vega C. Dissecting the Interaction Fingerprints and Binding Affinity of BYL719 Analogs Targeting PI3Kα. J Phys Chem B 2024; 128:1819-1829. [PMID: 38373112 DOI: 10.1021/acs.jpcb.3c06766] [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: 02/21/2024]
Abstract
Phosphatidylinositol-3-kinase Alpha (PI3Kα) is a lipid kinase which regulates signaling pathways involved in cell proliferation. Dysregulation of these pathways promotes several human cancers, pushing for the development of anticancer drugs to target PI3Kα. One such medicinal chemistry campaign at Novartis led to the discovery of BYL719 (Piqray, Alpelicib), a PI3Kα inhibitor approved by the FDA in 2019 for treatment of HR+/HER2-advanced breast cancer with a PIK3CA mutation. Structure-based drug design played a key role in compound design and optimization throughout the discovery process. However, further characterization of potency drivers via structural dynamics and energetic analyses can be advantageous for ensuing PI3Kα programs. Here, our goal is to employ various in-silico techniques, including molecular simulations and machine learning, to characterize 14 ligands from the BYL719 analogs and predict their binding affinities. The structural insights from molecular simulations suggest that although the ligand-hinge interaction is the primary driver of ligand stability at the pocket, the R group positioning at C2 or C6 of pyridine/pyrimidine also plays a major role. Binding affinities predicted via thermodynamic integration (TI) are in good agreement with previously reported IC50s. Yet, computationally demanding techniques such as TI might not always be the most efficient approach for affinity prediction, as in our case study, fast high-throughput techniques were capable of classifying compounds as active or inactive, and one docking approach showed accuracy comparable to TI.
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Affiliation(s)
- Sepehr Dehghani-Ghahnaviyeh
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Cihan Soylu
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Pascal Furet
- Novartis Institutes for BioMedical Research, CH4002 Basel, Switzerland
| | - Camilo Velez-Vega
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
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7
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Hu J, Fu S, Zhan Z, Zhang J. Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects. Eur J Med Chem 2024; 265:116109. [PMID: 38183777 DOI: 10.1016/j.ejmech.2023.116109] [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: 12/05/2023] [Revised: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 01/08/2024]
Abstract
Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.
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Affiliation(s)
- Jiarui Hu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Siyu Fu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zixuan Zhan
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
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8
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Nie S, Chang L, Huang Y, Zhou H, Yang Q, Kong L, Li Y. β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:3. [PMID: 38169019 PMCID: PMC10761647 DOI: 10.1007/s13659-023-00422-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 11/22/2023] [Indexed: 01/05/2024]
Abstract
Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.
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Affiliation(s)
- Shiyun Nie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Lizhong Chang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Ying Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Heyang Zhou
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Qianqing Yang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Lingmei Kong
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
| | - Yan Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
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9
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Acharya A, Yadav M, Nagpure M, Kumaresan S, Guchhait SK. Molecular medicinal insights into scaffold hopping-based drug discovery success. Drug Discov Today 2024; 29:103845. [PMID: 38013043 DOI: 10.1016/j.drudis.2023.103845] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 11/29/2023]
Abstract
In both academia and the pharmaceutical industry, innovative hypotheses, methodologies and technologies that can shorten the drug research and development, leading to higher success rates, are vital. In this review, we demonstrate how innovative variations of the scaffold-hopping strategy have been used to create new druggable molecular spaces, drugs, clinical candidates, preclinical candidates, and bioactive agents. We also analyze molecular modulations that enabled improvements of the pharmacodynamic (PD), physiochemical, and pharmacokinetic (PK) properties (P3 properties) of the drugs resulting from these scaffold-hopping strategies.
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Affiliation(s)
- Ayan Acharya
- National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India
| | - Mukul Yadav
- National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India
| | - Mithilesh Nagpure
- National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India
| | - Sanathanalaxmi Kumaresan
- National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India; National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India
| | - Sankar K Guchhait
- National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
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10
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Yang Y, Sun X, Luo L, Peng R, Yang R, Cheng Z, Lv Y, Li H, Tang Q, Zhu W, Qiao D, Xu S. Discovery of novel potent PI3K/mTOR dual-target inhibitors based on scaffold hopping: Design, synthesis, and antiproliferative activity. Arch Pharm (Weinheim) 2023; 356:e2300403. [PMID: 37840368 DOI: 10.1002/ardp.202300403] [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: 07/24/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/17/2023]
Abstract
The PI3K/AKT/mTOR pathway is one of the most common dysregulated signaling cascade responses in human cancers, playing a crucial role in cell proliferation and angiogenesis. Therefore, the development of anticancer drugs targeting the PI3K and mTOR pathways has become a research hotspot in cancer treatment. In this study, the PI3K selective inhibitor GDC-0941 was selected as a lead compound, and 28 thiophenyl-triazine derivatives with aromatic urea structures were synthesized based on scaffold hopping, serving as a novel class of PI3K/mTOR dual inhibitors. The most promising compound Y-2 was obtained through antiproliferative activity evaluation, kinase inhibition, and toxicity assays. The results showed that Y-2 demonstrated potential inhibitory effects on both PI3K kinase and mTOR kinase, with IC50 values of 171.4 and 10.2 nM, respectively. The inhibitory effect of Y-2 on mTOR kinase was 52 times greater than that of the positive drug GDC-0941. Subsequently, the antitumor activity of Y-2 was verified through pharmacological experiments such as AO staining, cell apoptosis, scratch assays, and cell colony formation. The antitumor mechanism of Y-2 was further investigated through JC-1 experiments, real-time quantitative PCR, and Western blot analysis. Based on the above experiments, Y-2 can be identified as a potent PI3K/mTOR dual inhibitor for cancer treatment.
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Affiliation(s)
- Yang Yang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Xin Sun
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Leixuan Luo
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Rujue Peng
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Ruiqing Yang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Zhenjie Cheng
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Yao Lv
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Hongfeng Li
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Qidong Tang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Wufu Zhu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Dan Qiao
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Shan Xu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
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11
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Tang J, Liu J, He X, Fu S, Wang K, Li C, Li Y, Zhu Y, Gong P, Zhao Y, Liu Y, Hou Y. Design and Synthesis of 1,3,5-Triazines or Pyrimidines Containing Dithiocarbamate Moiety as PI3Kα Selective Inhibitors. ACS Med Chem Lett 2023; 14:1266-1274. [PMID: 37736169 PMCID: PMC10510507 DOI: 10.1021/acsmedchemlett.3c00287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 08/03/2023] [Indexed: 09/23/2023] Open
Abstract
Recent studies have shown that phosphoinositide 3-kinase (PI3K) plays a vital role in cell division, and it has become a therapeutic target for many cancers. In this paper, some new 1,3,5-triazine or pyrimidine skeleton derivatives containing dithiocarbamate were designed and synthesized based on the reasonable drug design strategy from the previously effective compound 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK-474), in order to get effective selective PI3Kα inhibitors that have not been reported in the literature. In addition, the inhibitory activities of these compounds on PI3Kα and two tumor cell lines in vitro (HCT-116, U87-MG) were evaluated. The representative compound 13 showed a half-maximal inhibitory concentration (IC50) value of 1.2 nM for PI3Kα and an exciting kinase selectivity. Compound 13 displayed strong efficacy in HCT-116 and U87-MG cell lines with IC50 values of 0.83 and 1.25 μM, respectively. In addition, compound 13 induced obvious tumor regression in the U87-MG cell line xenografts mouse model, with no obvious signs of toxicity after intraperitoneal injection at a dose of 40 mg/kg. Compound 13 can be an effective selective inhibitor of PI3Kα, and it provides patients with an opportunity to avoid the side effects related to the wider inhibition of the class I PI3K family.
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Affiliation(s)
| | | | - Xinzi He
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Siyu Fu
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Kang Wang
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Chunting Li
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yuan Li
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yanli Zhu
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Ping Gong
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yanfang Zhao
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yajing Liu
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yunlei Hou
- School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
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12
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Orrapin S, Thongkumkoon P, Udomruk S, Moonmuang S, Sutthitthasakul S, Yongpitakwattana P, Pruksakorn D, Chaiyawat P. Deciphering the Biology of Circulating Tumor Cells through Single-Cell RNA Sequencing: Implications for Precision Medicine in Cancer. Int J Mol Sci 2023; 24:12337. [PMID: 37569711 PMCID: PMC10418766 DOI: 10.3390/ijms241512337] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Circulating tumor cells (CTCs) hold unique biological characteristics that directly involve them in hematogenous dissemination. Studying CTCs systematically is technically challenging due to their extreme rarity and heterogeneity and the lack of specific markers to specify metastasis-initiating CTCs. With cutting-edge technology, single-cell RNA sequencing (scRNA-seq) provides insights into the biology of metastatic processes driven by CTCs. Transcriptomics analysis of single CTCs can decipher tumor heterogeneity and phenotypic plasticity for exploring promising novel therapeutic targets. The integrated approach provides a perspective on the mechanisms underlying tumor development and interrogates CTCs interactions with other blood cell types, particularly those of the immune system. This review aims to comprehensively describe the current study on CTC transcriptomic analysis through scRNA-seq technology. We emphasize the workflow for scRNA-seq analysis of CTCs, including enrichment, single cell isolation, and bioinformatic tools applied for this purpose. Furthermore, we elucidated the translational knowledge from the transcriptomic profile of individual CTCs and the biology of cancer metastasis for developing effective therapeutics through targeting key pathways in CTCs.
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Affiliation(s)
- Santhasiri Orrapin
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Patcharawadee Thongkumkoon
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Sasimol Udomruk
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
| | - Sutpirat Moonmuang
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Songphon Sutthitthasakul
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Petlada Yongpitakwattana
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Dumnoensun Pruksakorn
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
- Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
| | - Parunya Chaiyawat
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
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13
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Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, Chen N. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238:1693-1715. [PMID: 37334436 DOI: 10.1002/jcp.31053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023]
Abstract
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.
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Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yongli Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Yuheng Liu
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoping Hu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Nan Chen
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
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14
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Gupta S, Paul K. Membrane-active substituted triazines as antibacterial agents against Staphylococcus aureus with potential for low drug resistance and broad activity. Eur J Med Chem 2023; 258:115551. [PMID: 37348297 DOI: 10.1016/j.ejmech.2023.115551] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 05/29/2023] [Accepted: 06/06/2023] [Indexed: 06/24/2023]
Abstract
A library of new naphthalimide-triazine analogues was synthesized as broad-spectrum antibacterial agents to overcome drug resistance. Bioactivity assay reveals that derivative 8e, with benzylamine in its structure, exhibits strong antibacterial properties against multi-drug resistance Staphylococcus aureus at a concentration of 1.56 μg/ml. It was also found to be better than chloromycin and amoxicillin. The active compound 8e efficiently inhibits the development of drug resistance within 11 passages. In addition, compound 8e inhibits the formation of biofilms in S. aureus and acts rapidly in bactericidal efficacy. Furthermore, mechanistic studies reveal that compound 8e effectively destroys the cytoplasmic membrane of bacteria, leading to leakage of intercellular protein content and loss in metabolic activity. Compound 8e binds to HSA readily with a binding constant of 1.32 × 105 M-1, indicating that the compound could be delivered to the target site effectively. Compound 8e can also form a supramolecular complex with DNA to obstruct DNA replications. These results suggest that analogue 8e could be further developed as a potential antibacterial agent. Furthermore, the cytotoxicity of all the synthesized compounds was evaluated against 60 human cancer cell lines to test their potential for anticancer agents.
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Affiliation(s)
- Saurabh Gupta
- School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala, 147001, India
| | - Kamaldeep Paul
- School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala, 147001, India.
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15
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Liebscher G, Vujic N, Schreiber R, Heine M, Krebiehl C, Duta-Mare M, Lamberti G, de Smet CH, Hess MW, Eichmann TO, Hölzl S, Scheja L, Heeren J, Kratky D, Huber LA. The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue. Mol Metab 2023; 71:101705. [PMID: 36907508 PMCID: PMC10074977 DOI: 10.1016/j.molmet.2023.101705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/28/2023] [Accepted: 03/06/2023] [Indexed: 03/13/2023] Open
Abstract
OBJECTIVE In brown adipose tissue (iBAT), the balance between lipid/glucose uptake and lipolysis is tightly regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) complex, which serves to translate the nutrient status of the cell to the respective kinase. However, the role of LAMTOR in metabolically active iBAT has been elusive. METHODS Using an AdipoqCRE-transgenic mouse line, we deleted LAMTOR2 (and thereby the entire LAMTOR complex) in adipose tissue (LT2 AKO). To examine the metabolic consequences, we performed metabolic and biochemical studies in iBAT isolated from mice housed at different temperatures (30 °C, room temperature and 5 °C), after insulin treatment, or in fasted and refed condition. For mechanistic studies, mouse embryonic fibroblasts (MEFs) lacking LAMTOR 2 were analyzed. RESULTS Deletion of the LAMTOR complex in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake, which led to massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was abrogated by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient MEFs. CONCLUSIONS We identified a homeostatic circuit for the maintenance of iBAT metabolism that links the LAMTOR-mTORC1 pathway to PI3K-mTORC2-AKT signaling downstream of the insulin receptor.
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Affiliation(s)
- Gudrun Liebscher
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Nemanja Vujic
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria
| | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria
| | - Markus Heine
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Caroline Krebiehl
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Madalina Duta-Mare
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria
| | - Giorgia Lamberti
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Cedric H de Smet
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Michael W Hess
- Institute of Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, 6020 Innsbruck, Austria
| | - Thomas O Eichmann
- Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria
| | - Sarah Hölzl
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Dagmar Kratky
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria; BioTechMed-Graz, Mozartgasse 12, 8010 Graz, Austria
| | - Lukas A Huber
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
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16
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Isoyama S, Tamaki N, Noguchi Y, Okamura M, Yoshimatsu Y, Kondo T, Suzuki T, Yaguchi SI, Dan S. Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors. Cell Death Dis 2023; 14:169. [PMID: 36849535 PMCID: PMC9971170 DOI: 10.1038/s41419-023-05690-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 03/01/2023]
Abstract
Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing's sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.
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Affiliation(s)
- Sho Isoyama
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Naomi Tamaki
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Yutaka Noguchi
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Mutsumi Okamura
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Yuki Yoshimatsu
- Department of Patient-derived Cancer Model, Tochigi Cancer Center, 4-9-13 Yohnan, Utsunomiya, Tochigi, 320-0834, Japan
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takeshi Suzuki
- Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan
| | - Shin-Ichi Yaguchi
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
- OHARA Pharmaceutical Co., Ltd., 36F St. Luke's Tower, 8-1 Akashi-cho, Chuo-ku, Tokyo, 104-6591, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
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17
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Hosomi H, Akatsuka A, Dan S, Iwasaki H, Nambu H, Kojima N. Synthesis of Acetogenin Analogs Comprising Pyrimidine Moieties Linked by Amine Bonds and Their Inhibitory Activity against Human Cancer Cell Lines. Chem Pharm Bull (Tokyo) 2022; 70:823-826. [DOI: 10.1248/cpb.c22-00574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
| | - Akinobu Akatsuka
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
| | - Shingo Dan
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
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18
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Wang Y, Liu Y, Ge T, Tang J, Wang S, Gao Z, Chen J, Xu J, Gong P, Zhao Y, Liu J, Hou Y. Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors. Bioorg Chem 2022; 130:106211. [DOI: 10.1016/j.bioorg.2022.106211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/29/2022] [Accepted: 10/13/2022] [Indexed: 11/17/2022]
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19
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Wang S, Tanaka Y, Xu Y, Takeda S, Hirokawa N. KIF3B promotes a PI3K signaling gradient causing changes in a Shh protein gradient and suppressing polydactyly in mice. Dev Cell 2022; 57:2273-2289.e11. [DOI: 10.1016/j.devcel.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 07/27/2022] [Accepted: 09/13/2022] [Indexed: 11/03/2022]
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20
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Radwan IT, Elwahy AH, Darweesh AF, Sharaky M, Bagato N, Khater HF, Salem ME. Design, synthesis, docking study, and anticancer evaluation of novel bis-thiazole derivatives linked to benzofuran or benzothiazole moieties as PI3k inhibitors and apoptosis inducers. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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21
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Jia W, Luo S, Zhao W, Xu W, Zhong Y, Kong D. Discovery of Novel PI3Kδ Inhibitors Based on the p110δ Crystal Structure. Molecules 2022; 27:molecules27196211. [PMID: 36234743 PMCID: PMC9571382 DOI: 10.3390/molecules27196211] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/10/2022] [Accepted: 09/14/2022] [Indexed: 12/03/2022] Open
Abstract
PI3Kδ is a key mediator of B-cell receptor signaling and plays an important role in the pathogenesis of certain hematological malignancies, such as chronic lymphocytic leukemia. Idelalisib, which targets PI3Kδ specifically, is the first approved PI3K inhibitor for cancer therapy. Recently, we carried out virtual screening, cell-based assays, adapta kinase assays, and molecular dynamic analysis to discover novel PI3Kδ inhibitors and identified NSC348884 as a lead PI3Kδ inhibitor. NSC348884 had an excellent docking score, potent PI3Kδ-inhibitory activity, antitumor effects on various cancer cell lines, and a favorable binding mode with the active site of PI3Kδ. Moreover, through the structural modification of NSC348884, we further discovered comp#1, which forms H-bonds with both Val828 and Lys779 in the ATP binding pocket of PI3Kδ, with a more favorable conformation binding to PI3Kδ. In addition, we found that N1, N1, N2-trimethyl-N2-((6-methyl-1H-benzo[d]imidazol-2-yl) methyl) ethane-1,2-diamine might be a potential scaffold structure. Thus, the result of this study provides a far more efficient approach for discovering novel inhibitors targeting PI3Kδ.
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Affiliation(s)
- Wenqing Jia
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Shuyu Luo
- School of Stomatology, Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, China
| | - Wennan Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Weiren Xu
- Tianjin Institute of Pharmaceutical Research, Tianjin 300070, China
| | - Yuxu Zhong
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
- Correspondence: (Y.Z.); (D.K.)
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China
- Correspondence: (Y.Z.); (D.K.)
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22
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Kunimasa K, Ikeda-Ishikawa C, Tani Y, Tsukahara S, Sakurai J, Okamoto Y, Koido M, Dan S, Tomida A. Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation. Sci Rep 2022; 12:11533. [PMID: 35798783 PMCID: PMC9262966 DOI: 10.1038/s41598-022-15673-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022] Open
Abstract
The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation.
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Affiliation(s)
- Kazuhiro Kunimasa
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Chika Ikeda-Ishikawa
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Yuri Tani
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Satomi Tsukahara
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Junko Sakurai
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Yuka Okamoto
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Masaru Koido
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.,Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Akihiro Tomida
- Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
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23
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Fath MK, Ebrahimi M, Nourbakhsh E, Hazara AZ, Mirzaei A, Shafieyari S, Salehi A, Hoseinzadeh M, Payandeh Z, Barati G. PI3K/Akt/mTOR Signaling Pathway in Cancer Stem Cells. Pathol Res Pract 2022; 237:154010. [DOI: 10.1016/j.prp.2022.154010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/21/2022] [Accepted: 06/29/2022] [Indexed: 12/30/2022]
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24
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New bioactive 1D Ag(I) coordination polymers with pyrazole and triazine ligands; Synthesis, X-ray structure, Hirshfeld analysis and DFT studies. Inorganica Chim Acta 2022. [DOI: 10.1016/j.ica.2022.120948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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25
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Ohta K, Fushimi T, Okamura M, Akatsuka A, Dan S, Iwasaki H, Yamashita M, Kojima N. Structure-antitumor activity relationship of hybrid acetogenins focusing on connecting groups between heterocycles and the linker moiety. RSC Adv 2022; 12:15728-15739. [PMID: 35685710 PMCID: PMC9131733 DOI: 10.1039/d2ra02399g] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/17/2022] [Indexed: 11/30/2022] Open
Abstract
We studied hybrid molecules of annonaceous acetogenins and mitochondrial complex I-inhibiting insecticides to develop a novel anticancer agent. A structure–antitumor activity relationship study focusing on the connecting groups between the heterocycles and the linker moiety bearing the tetrahydrofuran moiety was conducted. Eleven hybrid acetogenins with 1-methylpyrazole instead of γ-lactone were synthesized and their growth inhibitory activities against 39 human cancer cell lines were evaluated. The nitrogen atom at the 2′-position of the linker moiety was essential for inhibiting cancer growth. The 1-methylpyrazole-5-sulfonamide analog showed potent growth inhibition of NCI-H23, a human lung cancer cell line, in a xenograft mouse assay without critical toxicity. Hence, the results of this study may pave the way for the development of novel anticancer agents, with both selective and broad anticancer activities. The in vivo active 1-methylpyrazole-5-sulfonamide analog of acetogenins was obtained by the structure–antitumor activity relationship, focusing on the connecting groups between the heterocycle and the linker.![]()
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Affiliation(s)
- Kaito Ohta
- Kyoto Pharmaceutical University 1 Misasagi-Shichono-cho, Yamashina-ku Kyoto 607-8412 Japan
| | - Tetsuya Fushimi
- Graduate School of Pharmaceutical Sciences, Osaka University 1-6 Yamadaoka Suita Osaka 565-0871 Japan
| | - Mutsumi Okamura
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research 3-8-1 Ariake-ku Tokyo 135-8550 Japan
| | - Akinobu Akatsuka
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research 3-8-1 Ariake-ku Tokyo 135-8550 Japan
| | - Shingo Dan
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research 3-8-1 Ariake-ku Tokyo 135-8550 Japan
| | - Hiroki Iwasaki
- Kyoto Pharmaceutical University 1 Misasagi-Shichono-cho, Yamashina-ku Kyoto 607-8412 Japan
| | - Masayuki Yamashita
- Kyoto Pharmaceutical University 1 Misasagi-Shichono-cho, Yamashina-ku Kyoto 607-8412 Japan
| | - Naoto Kojima
- Kyoto Pharmaceutical University 1 Misasagi-Shichono-cho, Yamashina-ku Kyoto 607-8412 Japan
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26
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Fairhurst RA, Furet P, Imbach-Weese P, Stauffer F, Rueeger H, McCarthy C, Ripoche S, Oswald S, Arnaud B, Jary A, Maira M, Schnell C, Guthy DA, Wartmann M, Kiffe M, Desrayaud S, Blasco F, Widmer T, Seiler F, Gutmann S, Knapp M, Caravatti G. Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor. J Med Chem 2022; 65:8345-8379. [PMID: 35500094 DOI: 10.1021/acs.jmedchem.2c00267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.
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Affiliation(s)
- Robin A Fairhurst
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Pascal Furet
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | | | - Frédéric Stauffer
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Heinrich Rueeger
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Clive McCarthy
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Sebastien Ripoche
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Susanne Oswald
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Bertrand Arnaud
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Aline Jary
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Michel Maira
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Christian Schnell
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Daniel A Guthy
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Markus Wartmann
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Michael Kiffe
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | | | - Francesca Blasco
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Toni Widmer
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Frank Seiler
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Sascha Gutmann
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
| | - Mark Knapp
- Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States
| | - Giorgio Caravatti
- Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland
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27
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Xue YW, Itoh H, Dan S, Inoue M. Gramicidin A accumulates in mitochondria, reduces ATP levels, induces mitophagy, and inhibits cancer cell growth. Chem Sci 2022; 13:7482-7491. [PMID: 35872830 PMCID: PMC9241976 DOI: 10.1039/d2sc02024f] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/02/2022] [Indexed: 11/21/2022] Open
Abstract
Here we revealed the spatiotemporal behavior of gramicidin A in cancer cells. Gramicidin A depolarizes both the plasma and mitochondrial membranes, inhibits ATP synthesis, and induces mitophagy, thereby causing potent inhibition of cell growth.
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Affiliation(s)
- Yun-Wei Xue
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Hiroaki Itoh
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Masayuki Inoue
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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28
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Borsari C, Wymann MP. Targeting Phosphoinositide 3-Kinase - Five Decades of Chemical Space Exploration. Chimia (Aarau) 2021; 75:1037-1044. [PMID: 34920774 DOI: 10.2533/chimia.2021.1037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Phosphoinositide 3-kinase (PI3K) plays a key role in a plethora of physiologic processes and controls cell growth, metabolism, immunity, cardiovascular and neurological function, and more. The discovery of wort-mannin as the first potent PI3K inhibitor (PI3Ki) in the 1990s provided rapid identification of PI3K-dependent processes, which drove the discovery of the PI3K/protein kinase B (PKB/Akt)/target of rapamycin (mTOR) pathway. Genetic mouse models and first PI3K isoform-specific inhibitors pinpointed putative therapeutic applications. The recognition of PI3K as target for cancer therapy drove subsequently drug development. Here we provide a brief journey through the emerging roles of PI3K to the development of preclinical and clinical PI3Ki candidates.
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Affiliation(s)
- Chiara Borsari
- Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland
| | - Matthias P Wymann
- Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland;,
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29
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Kawatani M, Aono H, Shimizu T, Ohkura S, Hiranuma S, Muroi M, Ogawa N, Ohishi T, Ohba SI, Kawada M, Yamazaki K, Dan S, Osada H. Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth. ACS Chem Biol 2021; 16:2570-2580. [PMID: 34730931 DOI: 10.1021/acschembio.1c00625] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and is a promising cancer treatment target. This study reports the identification of indoluidin D and its derivatives as inhibitors of DHODH. Cell-based phenotypic screening revealed that indoluidin D promoted myeloid differentiation and inhibited the proliferation of acute promyelocytic leukemia HL-60 cells. Indoluidin D also suppressed cell growth in various other types of cancer cells. Cancer cell sensitivity profiling with JFCR39 and proteomic profiling with ChemProteoBase revealed that indoluidin D is a DHODH inhibitor. Indoluidin D inhibited human DHODH activity in vitro; the DHODH reaction product orotic acid rescued indoluidin D-induced cell differentiation. We synthesized several indoluidin D diastereomer derivatives and demonstrated that stereochemistry was vital to their molecular activity. The indoluidin D derivative indoluidin E showed similar activity to its parent compound and suppressed tumor growth in a murine lung cancer xenograft model. Hence, indoluidin D and its derivatives selectively inhibit DHODH and suppress cancer cell growth.
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Affiliation(s)
- Makoto Kawatani
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
- Chemical Resource Development Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Harumi Aono
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Takeshi Shimizu
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Shouta Ohkura
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Sayoko Hiranuma
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Makoto Muroi
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
- Chemical Resource Development Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Naoko Ogawa
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan
| | - Shun-ichi Ohba
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan
| | - Kanami Yamazaki
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japan Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japan Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Hiroyuki Osada
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
- Chemical Resource Development Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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30
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Ohta K, Akatsuka A, Dan S, Iwasaki H, Yamashita M, Kojima N. Structure-Activity Relationships of Thiophene Carboxamide Annonaceous Acetogenin Analogs: Shortening the Alkyl Chain in the Tail Part Significantly Affects Their Growth Inhibitory Activity against Human Cancer Cell Lines. Chem Pharm Bull (Tokyo) 2021; 69:1029-1033. [PMID: 34602571 DOI: 10.1248/cpb.c21-00450] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
In a previous study, we found that the thiophene carboxamide solamin analog, which is a mono-tetrahydrofuran annonaceous acetogenin, showed potent antitumor activity through the inhibition of mitochondrial complex I. In this study, we synthesized analogs with short alkyl chains instead of the n-dodecyl group in the tail part. We evaluated their growth inhibitory activities against human cancer cell lines. We found that the alkyl chain in the tail part plays an essential role in their activity.
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Affiliation(s)
| | - Akinobu Akatsuka
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
| | - Shingo Dan
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
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31
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Borsari C, De Pascale M, Wymann MP. Chemical and Structural Strategies to Selectively Target mTOR Kinase. ChemMedChem 2021; 16:2744-2759. [PMID: 34114360 PMCID: PMC8518124 DOI: 10.1002/cmdc.202100332] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Indexed: 11/08/2022]
Abstract
Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First-generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP-competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP-competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3-kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds' ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.
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Affiliation(s)
- Chiara Borsari
- Department of BiomedicineUniversity of BaselMattenstrasse 284058BaselSwitzerland
| | - Martina De Pascale
- Department of BiomedicineUniversity of BaselMattenstrasse 284058BaselSwitzerland
| | - Matthias P. Wymann
- Department of BiomedicineUniversity of BaselMattenstrasse 284058BaselSwitzerland
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32
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Isoyama S, Mori S, Sugiyama D, Kojima Y, Tada Y, Shitara K, Hinohara K, Dan S, Nishikawa H. Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal. J Immunother Cancer 2021; 9:jitc-2020-002279. [PMID: 34446575 PMCID: PMC8395371 DOI: 10.1136/jitc-2020-002279] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 01/21/2023] Open
Abstract
Background Immune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy. Methods The impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8+ T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays. Results Improved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8+ T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8+ T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8+ T cells, leading to the enhanced generation of tumor antigen-specific memory CD8+ T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8+ T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter. Conclusions PI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8+ T cell responses, illustrating a promising combination therapy.
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Affiliation(s)
- Sho Isoyama
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Kashiwa, Japan.,Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.,R&D Center, Zenyaku Kogyo Co Ltd, Tokyo, Japan
| | - Shigeyuki Mori
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Kashiwa, Japan.,R&D Center, Zenyaku Kogyo Co Ltd, Tokyo, Japan
| | - Daisuke Sugiyama
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kojima
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuko Tada
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kunihiko Hinohara
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Kashiwa, Japan .,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, Yang W, Tian C, Miao Z, Wang T, Yang S. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther 2021; 6:201. [PMID: 34054126 PMCID: PMC8165101 DOI: 10.1038/s41392-021-00572-w] [Citation(s) in RCA: 782] [Impact Index Per Article: 195.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/23/2021] [Accepted: 03/15/2021] [Indexed: 02/07/2023] Open
Abstract
Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.
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Affiliation(s)
- Lei Zhong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Yueshan Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Liang Xiong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Wenjing Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ming Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ting Yuan
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Wei Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Chenyu Tian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Zhuang Miao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Tianqi Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shengyong Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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34
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Ghorbani SS, Montazeri N, Zeydi MM, Ghane M. Synthesis and Investigation of the Antibacterial Activity of New Tris-Thiourea Derivatives. Pharm Chem J 2021. [DOI: 10.1007/s11094-021-02372-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Bansal Y, Minhas R, Singhal A, Arora RK, Bansal G. Benzimidazole: A Multifacted Nucelus for Anticancer Agents. CURR ORG CHEM 2021. [DOI: 10.2174/1385272825666210208141107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cancer is characterized by an uncontrolled proliferation of cells, dedifferentiation,
invasiveness and metastasis. Endothelial growth factor (eGF), insulin-like growth factor
(IGF), platelet-derived growth factor (PDGF), Fibroblast growth factor (FGF), Vascular endothelial
growth factor (VEGF), checkpoint kinase 1 & 2 ( Chk1 & Chk2), aurora kinases,
topoisomerases, histone deacetylators (HDAC), poly(ADP-Ribose)polymerase (PARP), farnesyl
transferases, RAS-MAPK pathway and PI3K-Akt-mTOR pathway, are some of the
prominent mediators implicated in the proliferation of tumor cells. Huge artillery of natural
and synthetic compounds as anticancer, which act by inhibiting one or more of the enzymes
and/or pathways responsible for the progression of tumor cells, is reported in the literature.
The major limitations of anticancer agents used in clinics as well as of those under development
in literature are normal cell toxicity and other side effects due to lack of specificity.
Hence, medicinal chemists across the globe have been working for decades to develop potent and safe anticancer
agents from natural sources as well as from different classes of heterocycles. Benzimidazole is one of the most important
and explored heteronucelus because of their versatility in biological actions as well as synthetic applications
in medicinal chemistry. The structural similarity of amino derivatives of benzimidazole with purines makes it a fascinating
nucleus for the development of anticancer, antimicrobial and anti-HIV agents. This review article is an attempt
to critically analyze various reports on benzimidazole derivatives acting on different targets to act as anticancer so as
to understand the structural requirements around benzimidazole nucleus for each target and enable medicinal chemists
to promote rational development of antitumor agents.
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Affiliation(s)
- Yogita Bansal
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147002, India
| | - Richa Minhas
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147002, India
| | - Ankit Singhal
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147002, India
| | - Radhey Krishan Arora
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147002, India
| | - Gulshan Bansal
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147002, India
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Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
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Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, 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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Popova NV, Jücker M. The Role of mTOR Signaling as a Therapeutic Target in Cancer. Int J Mol Sci 2021; 22:ijms22041743. [PMID: 33572326 PMCID: PMC7916160 DOI: 10.3390/ijms22041743] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.
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Affiliation(s)
- Nadezhda V. Popova
- Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997 Moscow, Russia;
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- Correspondence: ; Tel.: +49-(0)-40-7410-56339
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Hu J, Zhang Y, Tang N, Lu Y, Guo P, Huang Z. Discovery of novel 1,3,5-triazine derivatives as potent inhibitor of cervical cancer via dual inhibition of PI3K/mTOR. Bioorg Med Chem 2021; 32:115997. [PMID: 33440319 DOI: 10.1016/j.bmc.2021.115997] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 10/22/2022]
Abstract
This study describes the synthesis of novel 1,3,5-triazine derivatives as potent inhibitors of cervical cancer. The compounds were initially tested for inhibition of PI3K/mTOR, where they showed significant inhibitory activity. The top-ranking molecule (compound 6 h) was further tested against class I PI3K isoforms, such as PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, where it showed the most significant activity against PI3Kα. Compound 6 h was then tested for anti-cancer activity against triple-negative breast cancer cells (MDA-MB321), human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human liver cancer cells (HepG2), and it showed the greatest potency against HeLa cells. The effects of compound 6 h were further evaluated against the HeLa cells, where it showed significant attenuation of cell viability by inducing cell cycle arrest in the G1 phase. Compound 6 h induced apoptosis and reduced migration and invasion of HeLa cells. Western blotting analysis showed that 6 h inhibited PI3K and mTOR with positive modulation of Bcl-2 and Bax levels in HeLa cells. The effects of compound 6 h were also investigated in a tumour xenograft mouse model, where it showed reduction of tumour volume and weight. It also inhibited the PI3K/Akt/mTOR signalling cascade in xenograft tumour tissues, as evidenced by western blotting analysis. The results of the present study suggest the possible utility of the designed 1,3,5-triazine derivative as a potent inhibitor of cervical cancer.
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Affiliation(s)
- Junbo Hu
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Yanli Zhang
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Na Tang
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Yanju Lu
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Peng Guo
- Department of Pathology, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China
| | - Ziming Huang
- Department of Thyroid Breast Surgery, Maternal and Child Health Hospital of Hubei Province, No.745 Wuluo Road, Wuhan city, Hubei province 430070, China.
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Goulart TAC, Back DF, Moura E Silva S, Zeni G. Diorganyl Diselenides and Iron(III) Chloride Drive the Regio- and Stereoselectivity in the Selenation of Ynamides. J Org Chem 2021; 86:980-994. [PMID: 33259208 DOI: 10.1021/acs.joc.0c02480] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
We report here our results on the application of ynamides as substrates in the reactions with diorganyl dichalcogenides and iron(III) chloride to give selectively three different types of compounds: E-α-chloro-β-(organoselenyl)enamides, 4-(organochalcogenyl)oxazolones, and vinyl tosylates. The results reveal that the selectivity in the formation of products was obtained by controlling the functional groups directly bonded to the nitrogen atom of the ynamides. Thus, α-chloro-β-(organoselenyl) enamide derivatives were exclusively obtained when the TsN- and MsN-ynamides were treated with a mixture of diorganyl diselenides (1.0 equiv) and FeCl3 (3.0 equiv) in dichloroethane (DCE, 3 mL), at room temperature. The 4-(organochalcogenyl)oxazolones were selectively obtained with ynamides having an ester group, directly bonded to the nitrogen atom, upon treatment with a solution of FeCl3 (1.5 equiv) and diorganyl dichalcogenides (1.0 equiv) in dichloromethane (3 mL) at room temperature. Finally, vinyl tosylates were obtained from ynamides having an ester group, directly bonded to the nitrogen atom, by reaction with p-toluenesulfonic acid. We also studied the application of the prepared compounds as substrates for Suzuki and Sonogashira cross-coupling reactions.
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Sugiura T, Kamino H, Nariai Y, Murakawa Y, Kondo M, Kawakami M, Ikeda N, Uchio Y, Urano T. Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis. THE JOURNAL OF IMMUNOLOGY 2020; 205:3277-3290. [PMID: 33177160 DOI: 10.4049/jimmunol.1901429] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 10/08/2020] [Indexed: 11/19/2022]
Abstract
Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser473) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser473) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.
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Affiliation(s)
- Tomoko Sugiura
- Department of Biochemistry, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan; .,Department of Rheumatology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
| | - Hiroki Kamino
- Department of Biochemistry, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
| | - Yuko Nariai
- Department of Biochemistry, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
| | - Yohko Murakawa
- Department of Rheumatology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
| | - Masahiro Kondo
- Department of Rheumatology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
| | - Makoto Kawakami
- Japan Community Health Care Organization Tamatsukuri Hospital, Matsue, Shimane 699-0293, Japan; and
| | - Noboru Ikeda
- Japan Community Health Care Organization Tamatsukuri Hospital, Matsue, Shimane 699-0293, Japan; and
| | - Yuji Uchio
- Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
| | - Takeshi Urano
- Department of Biochemistry, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan
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Mahajan D, Sen S, Kuila B, Sharma A, Arora R, Sagar M, Mahapatra AR, Gawade LB, Dugar S. Discovery and Development of SPR519 as a Potent, Selective, and Orally Bioavailable Inhibitor of PI3Kα and mTOR Kinases for the Treatment of Solid Tumors. J Med Chem 2020; 63:11121-11130. [PMID: 32897703 DOI: 10.1021/acs.jmedchem.0c01061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Herein, we report the identification and preclinical profile of a lead compound 10, (SPR519) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC50 of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48 μM), and SKOV3 (0.50 μM). When administrated orally, it shows a considerably high plasma exposure (area under curve: 26,858 nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified lead compound demonstrates significant efficacy and bioavailability in ovarian and colon cancer xenograft models when evaluated for dose-ranging efficacy studies, at a dose as low as 2.5 mg/kg.
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Affiliation(s)
- Dinesh Mahajan
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
| | - Somdutta Sen
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
| | - Bilash Kuila
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
| | - Amit Sharma
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
| | - Reena Arora
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
| | - Milind Sagar
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
| | - Amal Ray Mahapatra
- Sphaera Pharma Pvt. Ltd., Plot 32, Sec 5, IMT Manesar, Haryana 122051, India
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Ma W, Zhang Q, Li X, Ma Y, Liu Y, Hu S, Zhou Z, Zhang R, Du K, Syed A, Yao X, Chen P. IPM712, a vanillin derivative as potential antitumor agents, displays better antitumor activity in colorectal cancers cell lines. Eur J Pharm Sci 2020; 152:105464. [PMID: 32668313 DOI: 10.1016/j.ejps.2020.105464] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC), a major health threat in the world, ranks third in incidence and second in mortality among cancers. Chemotherapy, an important treatment for colorectal cancer, have be limited in the clinic due to the resistance and side effect. Studies have shown that PI3K-related regulatory pathways play a colossal role in colorectal cancer. Therefore, it is a good strategy to find a new drug which works by affecting the PI3K signaling pathway. In this paper, we obtained a new vanillin derivative (IPM712) by modifying the structure of IPM711 and tested its anticancer activity in vitro and toxicity in vivo. Results showed that IPM712 has a better anticancer activity than 5-Fu in HCT116 and SW480 cell lines. Furthermore, IPM712 can inhibit cell proliferation, migration and induce the apoptosis by affecting PI3K-related protein expression. Acute toxicity experiments show that IPM712 has no significant toxicity at therapeutic concentrations. Based on these results, IPM712 is a promising anticancer drug candidate for human colorectal cancer therapy.
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Affiliation(s)
- Wantong Ma
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Qianqian Zhang
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Xue Li
- College of Chemistry and Chemical Engineering, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, PR China
| | - Yunhao Ma
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Yuheng Liu
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Shujian Hu
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Zhongkun Zhou
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Rentao Zhang
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Kangjia Du
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Ashikujaman Syed
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Xiaojun Yao
- Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, PR China
| | - Peng Chen
- School of Pharmacy, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China.
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Liu J, Tan X, Zhao W, Liu J, Xing X, Fan G, Zhang P, Zhang Z, Zhong Y, Kong D. In Vitro and In Vivo Antimetastatic Effects of ZSTK474 on Prostate Cancer DU145 Cells. Curr Cancer Drug Targets 2020; 19:321-329. [PMID: 30205797 DOI: 10.2174/1568009618666180911101310] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/15/2018] [Accepted: 06/22/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND The lethality of prostate cancer is mainly due to metastasis. Inhibition of metastasis is expected to be a promising approach for prostate cancer therapy. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway is reported to be closely involved in cell growth, migration, etc. Objective: The study investigated the antimetastatic activities of pan-PI3K inhibitor ZSTK474 on DU145 cells. METHODS 1. The In vitro effect of ZSTK474 on the migration, invasion and adhesion of DU145 cells was determined with Transwell migration assay and wound healing assay, Tranwell invasion assay and adhesion assay, respectively. 2. In vitro effect of ZSTK474 on the signal proteins in DU145 cells was determined with Western blot analysis and ELISA. 3. Moreover, the In vivo antimetastatic effect of ZSTK474 was evaluated with MicroCT and histology analysis. RESULTS ZSTK474 potently attenuated the capability of migration, invasion and adhesion of DU145 cells, negatively regulated Girdin, Integrinβ1 and matrix metalloproteinases (MMPs). In addition, the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), which are known to be related to angiogenesis and metastasis, was also inhibited. Oral administration of ZSTK474 (200 mg/kg) ameliorated in vivo bone metastasis of DU145 cells, with improved bone structure and bone mineral density (BMD). Tissue staining indicated a reduction in metastatic DU145 cells and osteoclasts in the bones of ZSTK474-treated mice, compared with the non-treated group. CONCLUSION Our result demonstrated the antimetastatic activity of ZSTK474 on prostate cancer DU145 cells, suggesting the potential application in prostate cancer patients.
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Affiliation(s)
- Jie Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xiao Tan
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Wennan Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jing Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Xiaoxue Xing
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Guanwei Fan
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Ping Zhang
- Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yuxu Zhong
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
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Guo H, Diao QP. 1,3,5-Triazine-azole Hybrids and their Anticancer Activity. Curr Top Med Chem 2020; 20:1481-1492. [DOI: 10.2174/1568026620666200310122741] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/12/2020] [Accepted: 02/17/2020] [Indexed: 12/24/2022]
Abstract
1,3,5-Triazine and azole can interact with various therapeutic targets, and their derivatives
possess promising in vitro and in vivo anticancer activity. Hybrid molecules have the potential to enhance
efficiency, overcome drug resistance and reduce side effects, and many hybrid molecules are under
different phases of clinical trials, so hybridization of 1,3,5-triazine with azole may provide valuable
therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop
azole-containing 1,3,5-triazine hybrids as novel anticancer agents, and some of them exhibited excellent
activity. This review emphasizes azole-containing 1,3,5-triazine hybrids with potential anticancer activity,
and the structure-activity relationships as well as the mechanisms of action are also discussed to
provide comprehensive and target-oriented information for the development of this kind of anticancer
drugs.
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Affiliation(s)
- Hua Guo
- School of Chemistry and Life Science, Anshan Normal University, Anshan, Liaoning, China
| | - Quan-Ping Diao
- School of Chemistry and Life Science, Anshan Normal University, Anshan, Liaoning, China
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Wu TT, Guo QQ, Chen ZL, Wang LL, Du Y, Chen R, Mao YH, Yang SG, Huang J, Wang JT, Wang L, Tang L, Zhang JQ. Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors. Eur J Med Chem 2020; 204:112637. [PMID: 32717477 DOI: 10.1016/j.ejmech.2020.112637] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/29/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022]
Abstract
A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures of known anti-cancer agents, namely gedatolisib and alpelisib. All the target compounds were screened for inhibitory activity against PI3Kα and mTOR kinases. Notably, most analogs exhibited IC50 in the nanomolar range. Investigation of the isozyme selectivity indicated that the compounds exhibited remarkable inhibitory activity against PI3Kδ, especially compound 19f showed an IC50 value of 2.3 nM for PI3Kδ and moderate δ-isozyme selectivity over other class I PI3K isoforms and mTOR (with IC50 values of 14.6, 34.0, 849.0 and 15.4 nM for PI3Kα, β, γ and mTOR, respectively). An in vitro MTT assay was conducted to assess the antiproliferative and cytotoxic effects of the prepared analogs. It was revealed that the compounds displayed significant inhibitory activities against the HCT116 human colon cancer cell line. Compound 19i showed 4.7-fold higher potency than the positive control gedatolisib (0.3 vs. 1.4 μM, IC50 values). Phosphoblot studies demonstrated that 19c and 19i could significantly suppress the PI3K/Akt/mTOR signaling pathway at 10 μM. Moreover, analogs 19b, 19c and 19i displayed better stability in artificial gastric fluids than gedatolisib, while 19i was indicated not very stable in rat liver microsomes, and may occur phase I metabolic transformations.
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Affiliation(s)
- Ting-Ting Wu
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Qing-Qing Guo
- Joint International Research Laboratory of Synthetic Biology and Medicine, Ministry of Education, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Zi-Li Chen
- The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Li-Li Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Yao Du
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Rui Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Yuan-Hu Mao
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Sheng-Gang Yang
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Jing Huang
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Jian-Ta Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Ling Wang
- Joint International Research Laboratory of Synthetic Biology and Medicine, Ministry of Education, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China.
| | - Lei Tang
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China
| | - Ji-Quan Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China.
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Jia WQ, Feng XY, Liu YY, Han ZZ, Jing Z, Xu WR, Cheng XC. Identification of Phosphoinositide-3 Kinases Delta and Gamma Dual Inhibitors Based on the p110δ/γ Crystal Structure. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180816666190730163431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Phosphoinositide-3 kinases (PI3Ks) are key signaling molecules that affect
a diverse array of biological processes in cells, including proliferation, differentiation, survival, and
metabolism. The abnormal activity of PI3K signals is closely related to the occurrence of many diseases,
which has become a very promising drug target, especially for the treatment of cancer.
PI3Kδ/γ inhibitors can reduce toxicity concerns for chronic indications such as asthma and rheumatoid
arthritis compared with pan PI3Ks inhibitors.
Methods:
With the aim of finding more effective PI3Kδ/γ dual inhibitors, virtual screening,
ADMET prediction Molecular Dynamics (MD) simulations and MM-GBSA were executed based
on the known p110δ/γ crystal structure. Compound ZINC28564067 with high docking score and
low toxicity was obtained.
Results:
By MD simulations and MM-GBSA, we could observe that ZINC28564067 had more favorable
conformation binding to the PI3Kδ/γ than the original ligands.
Conclusion:
The results provided a rapid approach for the discovery of novel PI3Kδ/γ dual inhibitors
which might be a potential anti-tumor lead compound.
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Affiliation(s)
- Wen-Qing Jia
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Xiao-Yan Feng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Ya-Ya Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Zhen-Zhen Han
- Baokang Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Zhi Jing
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Wei-Ren Xu
- Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
| | - Xian-Chao Cheng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
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Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo[2,1-f][1,2,4]triazine derivatives. Bioorg Med Chem Lett 2020; 30:127194. [PMID: 32317209 DOI: 10.1016/j.bmcl.2020.127194] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/07/2020] [Accepted: 04/11/2020] [Indexed: 11/23/2022]
Abstract
A series of 6-aminocarbonyl pyrrolo[2,1-f][1,2,4]triazine derivatives were designed by scaffold hopping strategy. The IC50 values of compound 14a against PI3Ks were measured, showing selective activity against p110α and p110δ with IC50s of 122 nM and 119 nM respectively. All the synthesized compounds were evaluated for their antiproliferative activity against human cancer cells by SRB assay. Compounds 14a, 14p and 14q exhibited potent antiproliferative activity against five types of human cancer cells and the PK property of 14q was also investigated here.
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Ye T, Han Y, Wang R, Yan P, Chen S, Hou Y, Zhao Y. Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents. Bioorg Chem 2020; 99:103796. [PMID: 32283346 DOI: 10.1016/j.bioorg.2020.103796] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/05/2020] [Accepted: 03/24/2020] [Indexed: 01/18/2023]
Abstract
To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A12 showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC50 values of 3.24 μM, 14.37 μM, 7.39 μM, 7.10 μM, and 16.85 μM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A12. The results showed that compound A12 obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.
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Affiliation(s)
- Tianyu Ye
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | - Yufei Han
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | - Ruxin Wang
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | - Pingzhen Yan
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | - Shaowei Chen
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | - Yunlei Hou
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
| | - Yanfang Zhao
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
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González-Ruiz L, González-Moles MÁ, González-Ruiz I, Ruiz-Ávila I, Ayén Á, Ramos-García P. An update on the implications of cyclin D1 in melanomas. Pigment Cell Melanoma Res 2020; 33:788-805. [PMID: 32147907 DOI: 10.1111/pcmr.12874] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 02/03/2020] [Accepted: 03/02/2020] [Indexed: 12/13/2022]
Abstract
Cyclin D1 is a protein encoded by the CCND1 gene, located on 11q13 chromosome, which is a key component of the physiological regulation of the cell cycle. CCND1/cyclin D1 is upregulated in several types of human tumors including melanoma and is currently classified as an oncogene that promotes uncontrolled cell proliferation. Despite the demonstrated importance of CCND1/cyclin D1 as a central oncogene in several types of human tumors, its knowledge in melanoma is still limited. This review examines data published on upregulation of the CCND1 gene and cyclin D1 protein in the melanoma setting, focusing on the pathways and molecular mechanisms involved in the activation of the gene and on the clinical and therapeutic implications.
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Affiliation(s)
- Lucia González-Ruiz
- Dermatology Service, Ciudad Real General University Hospital, Ciudad Real, Spain
| | | | | | - Isabel Ruiz-Ávila
- Biohealth Research Institute, Granada, Spain.,Pathology Service, San Cecilio Hospital Complex, Granada, Spain
| | - Ángela Ayén
- Dermatology Service, San Cecilio Hospital Complex, Granada, Spain
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Matsumoto T, Akatsuka A, Dan S, Iwasaki H, Yamashita M, Kojima N. Synthesis and cancer cell growth inhibition effects of acetogenin analogs bearing ethylene glycol units for enhancing the water solubility. Tetrahedron 2020. [DOI: 10.1016/j.tet.2020.131058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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