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1
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Elsakka MEG, Tawfik MM, Barakat LAA, Nafie MS. A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition. J Biomol Struct Dyn 2024:1-19. [PMID: 38486408 DOI: 10.1080/07391102.2024.2327538] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 03/03/2024] [Indexed: 03/25/2025]
Abstract
Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC50 values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC50 values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor.
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Affiliation(s)
- Mayada E G Elsakka
- Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Mohamed M Tawfik
- Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Lamiaa A A Barakat
- Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Mohamed S Nafie
- Department of Chemistry, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
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2
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Abstract
For many years, antibody drug conjugates (ADC) have teased with the promise of targeted payload delivery to diseased cells, embracing the targeting of the antibody to which a cytotoxic payload is conjugated. During the past decade this promise has started to be realised with the approval of more than a dozen ADCs for the treatment of various cancers. Of these ADCs, brentuximab vedotin really laid the foundations of a template for a successful ADC with lysosomal payload release from a cleavable dipeptide linker, measured DAR by conjugation to the Cys-Cys interchain bonds of the antibody and a cytotoxic payload. Using this ADC design model oncology has now expanded their repertoire of payloads to include non-cytotoxic compounds. These new payload classes have their origins in prior medicinal chemistry programmes aiming to design selective oral small molecule drugs. While this may not have been achieved, the resulting compounds provide excellent starting points for ADC programmes with some compounds amenable to immediate linker attachment while for others extensive SAR and structural information offer invaluable design insights. Many of these new oncology payload classes are of interest to other therapeutic areas facilitating rapid access to drug-linkers for exploration as non-oncology ADCs. Other therapeutic areas have also pursued unique payload classes with glucocorticoid receptor modulators (GRM) being the most clinically advanced in immunology. Here, ADC payloads come full circle, as oncology is now investigating GRM payloads for the treatment of cancer. This chapter aims to cover all these new ADC approaches while describing the medicinal chemistry origins of the new non-cytotoxic payloads.
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Affiliation(s)
- Adrian D Hobson
- Small Molecule Therapeutics & Platform Technologies, AbbVie Bioresearch Center, Worcester, MA, United States.
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3
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Castillo Ordoñez WO, Aristizabal-Pachon AF, Alves LB, Giuliatti S. Epigenetic regulation exerted by Caliphruria subedentata and galantamine: an in vitro and in silico approach for mimic Alzheimer's disease. J Biomol Struct Dyn 2023; 42:11215-11230. [PMID: 37814967 DOI: 10.1080/07391102.2023.2261034] [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: 04/18/2023] [Accepted: 09/13/2023] [Indexed: 10/11/2023]
Abstract
At the interface between genes and environment, epigenetic mechanisms, including DNA methylation and histone modification, regulate neurogenic processes such as differentiation, proliferation, and maturation of neural stem cells. However, these mechanisms are altered in Alzheimer's disease (AD), a neurodegenerative condition that mainly affects older adults. Since epigenetic mechanisms are known to be reversible, a number of molecules from natural sources are being studied as epigenetic regulators in AD. Recently, in vitro and in silico studies have shown that C. subedentata and its alkaloids modulated neurotoxicity. However, studies exploring the epigenetic activity of these alkaloids are limited. We conducted a set of bioassays to evaluate neuronal differentiation and the sensitivity of undifferentiated SH-SY5 cells against a neurotoxic stimulus. In addition, we analyzed the methylation profiles in genes such as APP, PSI, and BACE1 due to their role in amyloid processing. Docking and molecular dynamic analysis were used to explore the effect exerted by C. subedentata alkaloids on the regulation of histone deacetylases (HDAC2, HDAC3 and HDAC7). The results demonstrated that C. subedentata and galantamine induce neuronal differentiation and protect the undifferentiated SH-SY5Y cells against Aβ(1-42)-induced neurotoxicity. The methylation profiles of the studied genes show no statistically significant differences between C. subedentata, galantamine. However, these findings should be interpreted with caution, since small changes in methylation promoters in the brain could not be easily detected. Results from in silico approaches describe for the first time the potential promissing epigenetic effects of galantamine by regulating HDAC3 and HDAC7 modification.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Willian Orlando Castillo Ordoñez
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología, Universidad del Cauca, Popayán-Cauca, Colombia
- Departamento de Estudios Psicológicos, Universidad Icesi, Cali, Colombia
| | - Andrés F Aristizabal-Pachon
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Levy Bueno Alves
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo-USP, Brazil
| | - Silvana Giuliatti
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo-USP, Brazil
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Quaas CE, Long DT. Targeting (de)acetylation: A Diversity of Mechanism and Disease. COMPREHENSIVE PHARMACOLOGY 2022:469-492. [DOI: 10.1016/b978-0-12-820472-6.00076-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Inhibition of HDACs Suppresses Cell Proliferation and Cell Migration of Gastric Cancer by Regulating E2F5 Targeting BCL2. Life (Basel) 2021; 11:life11121425. [PMID: 34947956 PMCID: PMC8705834 DOI: 10.3390/life11121425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/07/2021] [Accepted: 12/14/2021] [Indexed: 01/20/2023] Open
Abstract
(1) Background: Gastric cancer (GC) is the most common high death-rate cancer type worldwide, with an enhanced prevalence and increased rate of mortality. Although significant evidence on surgery strategy has been generated for the treatment of GC, conclusions are still uncertain regarding profound metastatic or persevering gastric cancer. Therefore, it is essential to develop novel and effective biomarkers or therapeutic targets for the diagnosis of GC. Histone deacetylations (HDACs) are important epigenetic regulators that control the aberrant transcription of critical genes that are mainly involved in cell proliferation, cell migration, regulation of the cell cycle, and different signal pathways. (2) Methods: Expression analysis of HDACs family members and E2F5 in gastric cancer cell lines was determined by RT-PCR and Western blotting. The cell proliferation was determined through an MTT assay. Cell migration was determined using a wound-healing assay. Flow cytometry experiments were used to determine cell-cycle analysis. The statistical software OriginPro 2015 (OriginLab, Northampton, MA, USA) was used to analyze data. A p value of < 0.05 was regarded as significant. (3) Results: The present study shows that E2F5 expression is upregulated in GC cancer cell lines compared to normal cell lines, and is positively associated with the level of HDACs and BCL2. HDACi and knocking down of E2F5 as tumor suppressors inhibited cell proliferation, migration invasion, and blocked the cell cycle in gastric cancer cells by suppressing BCL2. The results conclude that the anticancer mechanism of HDACi was determined by regulating E2F5 via targeting BCL2. (4) Conclusions: Our results suggest that the HDAC–E2F5–BCL2 signaling axis might be a novel potential biomarker in gastric cancer.
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Wang J, Cao Z, Wang F, Wang P, An J, Fu X, Liu T, Li Y, Li Y, Zhao Y, Lin H, He B. Cysteine derivatives as acetyl lysine mimics to inhibit zinc-dependent histone deacetylases for treating cancer. Eur J Med Chem 2021; 225:113799. [PMID: 34500130 DOI: 10.1016/j.ejmech.2021.113799] [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] [Received: 06/16/2021] [Revised: 08/09/2021] [Accepted: 08/22/2021] [Indexed: 12/12/2022]
Abstract
Zinc-dependent histone deacetylases (HDACs) are important epigenetic regulators that have become important drug targets for treating cancer. Although five HDAC inhibitors have been approved for treating several cancers, there is still a huge demand on discovering new HDAC inhibitors to explore the therapeutic potentials for treating solid tumor cancers. Substrate mimics are a powerful rational design approach for the development of potent inhibitors. Here we describe the rational design, synthesis, biological evaluation, molecular docking and in vivo efficacy study of a class of HDAC inhibitors using Nε-acetyl lysine mimics that are derived from cysteine. As a result, compounds 7a, 9b and 13d demonstrated pan-HDAC inhibition and broad cytotoxicity against several cancer cell lines, comparable to the approved HDAC inhibitor SAHA. Furthermore, 13d significantly inhibited tumor growth in a A549 xenograft mice model without any obvious weight loss, supporting that the cysteine-derived acetyl lysine mimics are promising HDAC inhibitors with therapeutic potentials for treating cancer.
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Affiliation(s)
- Jie Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Zhuoxian Cao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Fang Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Pan Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Jianxiong An
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Xiaozhong Fu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Ting Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Yan Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Yongjun Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Yonglong Zhao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China
| | - Hening Lin
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, United States
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China.
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7
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Cao Z, Yang F, Wang J, Gu Z, Lin S, Wang P, An J, Liu T, Li Y, Li Y, Lin H, Zhao Y, He B. Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer. J Med Chem 2021; 64:15280-15296. [PMID: 34624191 DOI: 10.1021/acs.jmedchem.1c01311] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.
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Affiliation(s)
- Zhuoxian Cao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Fenfen Yang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Jie Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Zhicheng Gu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Shuxian Lin
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Pan Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Jianxiong An
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Ting Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Yan Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Yongjun Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Hening Lin
- Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
| | - Yonglong Zhao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
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8
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Xiong Y, Donovan KA, Eleuteri NA, Kirmani N, Yue H, Razov A, Krupnick NM, Nowak RP, Fischer ES. Chemo-proteomics exploration of HDAC degradability by small molecule degraders. Cell Chem Biol 2021; 28:1514-1527.e4. [PMID: 34314730 PMCID: PMC9339248 DOI: 10.1016/j.chembiol.2021.07.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 12/25/2022]
Abstract
Targeted protein degradation refers to the use of small molecules that recruit a ubiquitin ligase to a target protein for ubiquitination and subsequent proteasome-dependent degradation. While degraders have been developed for many targets, key questions regarding degrader development and the consequences of acute pharmacological degradation remain, specifically for targets that exist in obligate multi-protein complexes. Here, we synthesize a pan-histone deacetylase (HDAC) degrader library for the chemo-proteomic exploration of acute degradation of a key class of chromatin-modifying enzymes. Using chemo-proteomics, we not only map the degradability of the zinc-dependent HDAC family identifying leads for targeting HDACs 1-8 and 10 but also explore important aspects of degrading epigenetic enzymes. We discover cell line-driven target specificity and that HDAC degradation often results in collateral loss of HDAC-containing repressive complexes. These findings potentially offer a new mechanism toward controlling chromatin structure, and our resource will facilitate accelerated degrader design and development for HDACs.
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Affiliation(s)
- Yuan Xiong
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Katherine A Donovan
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Nicholas A Eleuteri
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nadia Kirmani
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Hong Yue
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Anthony Razov
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Noah M Krupnick
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Radosław P Nowak
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Eric S Fischer
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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9
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Yepes AF, Arias JD, Cardona-G W, Herrera-R A, Moreno G. New class of hybrids based on chalcone and melatonin: a promising therapeutic option for the treatment of colorectal cancer. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02805-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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10
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Hassan EA, Mostafa HM, Zayed SE. A new utility of 1,3,3-tri(1 H-indol-3-yl)propan-1-one as a precursor for synthesizing of oxoketene gem-dithiol and 1,2-dithiole-3-thione, using eco-friendly lemon juice as a catalyst. PHOSPHORUS SULFUR 2021. [DOI: 10.1080/10426507.2020.1854756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Entesar A. Hassan
- Faculty of science, Chemistry Department, South Valley University, Qena, Egypt
| | - Hadir M. Mostafa
- Faculty of science, Chemistry Department, South Valley University, Qena, Egypt
| | - Salem E. Zayed
- Faculty of science, Chemistry Department, South Valley University, Qena, Egypt
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11
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Baghery S, Zarei M, Zolfigol MA, Mallakpour S, Behranvand V. Application of trityl moieties in chemical processes: part I. JOURNAL OF THE IRANIAN CHEMICAL SOCIETY 2020. [DOI: 10.1007/s13738-020-01980-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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12
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Dhuguru J, Skouta R. Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents. Molecules 2020; 25:E1615. [PMID: 32244744 PMCID: PMC7181244 DOI: 10.3390/molecules25071615] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/24/2020] [Accepted: 03/30/2020] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.
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Affiliation(s)
| | - Rachid Skouta
- Department of Biology, University of Massachusetts, Amherst, MA 01003, USA;
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13
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Zhang S, Gong Z, Oladimeji PO, Currier DG, Deng Q, Liu M, Chen T, Li Y. A high-throughput screening identifies histone deacetylase inhibitors as therapeutic agents against medulloblastoma. Exp Hematol Oncol 2019; 8:30. [PMID: 31788346 PMCID: PMC6858705 DOI: 10.1186/s40164-019-0153-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/04/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Medulloblastoma is the most frequently occurring malignant brain tumor in children. Current treatment strategies for medulloblastoma include aggressive surgery, cranio-spinal irradiation and adjuvant chemotherapy. Because current treatments can cause severe long-term side effects and are not curative, successful treatment remains a challenge. METHODS In this study, we employed a high-throughput cell viability assay to screen 12,800 compounds and to identify drug candidates with anti-proliferative properties for medulloblastoma cells. We also tested these compounds for attenuating medulloblastoma tumor development using mouse xenografts. RESULTS We identified two histone deacetylase inhibitors (dacinostat and quisinostat) with anti-proliferative properties for medulloblastoma cells. We showed that both compounds induce cytotoxicity, trigger cell apoptosis, and block cell cycle progression at the G2/M phase. In addition, dacinostat and quisinostat attenuated xenograft medulloblastoma growth in mice. CONCLUSIONS Our findings suggest that histone deacetylase inhibitors are potent therapeutic agents against medulloblastoma.
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Affiliation(s)
- Shanshan Zhang
- Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaojian Gong
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Peter O. Oladimeji
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Duane G. Currier
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Qipan Deng
- Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
| | - Ming Liu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Yong Li
- Section of Epidemiology & Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH USA
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14
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Zhao LM, Zhang JH. Histone Deacetylase Inhibitors in Tumor Immunotherapy. Curr Med Chem 2019; 26:2990-3008. [PMID: 28762309 DOI: 10.2174/0929867324666170801102124] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 04/26/2017] [Accepted: 06/27/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND With an increasing understanding of the antitumor immune response, considerable progress has been made in the field of tumor immunotherapy in the last decade. Inhibition of histone deacetylases represents a new strategy in tumor therapy and histone deacetylase inhibitors have been recently developed and validated as potential antitumor drugs. In addition to the direct antitumor effects, histone deacetylase inhibitors have been found to have the ability to improve tumor recognition by immune cells that may contribute to their antitumor activity. These immunomodolutory effects are desirable, and their in-depth comprehension will facilitate the design of novel regimens with improved clinical efficacy. OBJECTIVE Our goal here is to review recent developments in the application of histone deacetylase inhibitors as immune modulators in cancer treatment. METHODS Systemic compilation of the relevant literature in this field. RESULTS & CONCLUSION In this review, we summarize recent advances in the understanding of how histone deacetylase inhibitors alter immune process and discuss their effects on various cytokines. We also discuss the challenges to optimize the use of these inhibitors as immune modulators in cancer treatment. Information gained from this review will be valuable to this field and may be helpful for designing tumor immunotherapy trials involving histone deacetylase inhibitors.
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Affiliation(s)
- Li-Ming Zhao
- School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.,State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, Guangxi, China
| | - Jie-Huan Zhang
- School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
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15
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Aboukhatwa SM, Hanigan TW, Taha TY, Neerasa J, Ranjan R, El-Bastawissy EE, Elkersh MA, El-Moselhy TF, Frasor J, Mahmud N, McLachlan A, Petukhov PA. Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue. ChemMedChem 2019; 14:1096-1107. [PMID: 30921497 PMCID: PMC6548601 DOI: 10.1002/cmdc.201900114] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/28/2019] [Indexed: 01/27/2023]
Abstract
Histone deacetylase (HDAC) activity is modulated in vivo by post-translational modifications and formation of multiprotein complexes. Novel chemical tools to study how these factors affect engagement of HDAC isoforms by HDAC inhibitors (HDACi) in cells and tissues are needed. In this study, a synthetic strategy to access chemically diverse photoreactive probes (PRPs) was developed and used to prepare seven novel HDAC PRPs 9-15. The class I HDAC isoform engagement by PRPs was determined in biochemical assays and photolabeling experiments in live SET-2, HepG2, HuH7, and HEK293T cell lines and in mouse liver tissue. Unlike the HDAC protein abundance and biochemical activity against recombinant HDACs, the chemotype of the PRPs and the type of cells were key in defining the engagement of HDAC isoforms in live cells. Our findings suggest that engagement of HDAC isoforms by HDACi in vivo may be substantially modulated in a cell- and tissue-type-dependent manner.
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Affiliation(s)
- Shaimaa M Aboukhatwa
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Thomas W Hanigan
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA
| | - Taha Y Taha
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA
| | - Jayaprakash Neerasa
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA
| | - Rajeev Ranjan
- Section of Hematology/Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Eman E El-Bastawissy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Mohamed A Elkersh
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University, Alexandria, 21311, Egypt
| | - Tarek F El-Moselhy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Jonna Frasor
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Nadim Mahmud
- Section of Hematology/Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Alan McLachlan
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Pavel A Petukhov
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA
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16
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Alam MA. Methods for Hydroxamic Acid Synthesis. CURR ORG CHEM 2019; 23:978-993. [PMID: 32565717 PMCID: PMC7304568 DOI: 10.2174/1385272823666190424142821] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 03/20/2019] [Accepted: 03/28/2019] [Indexed: 12/26/2022]
Abstract
Substituted hydroxamic acid is one of the most extensively studied pharmacophores because of their ability to chelate biologically important metal ions to modulate various enzymes, such as HDACs, urease, metallopeptidase, and carbonic anhydrase. Syntheses and biological studies of various classes of hydroxamic acid derivatives have been reported in numerous research articles in recent years but this is the first review article dedicated to their synthetic methods and their application for the synthesis of these novel molecules. In this review article, commercially available reagents and preparation of hydroxylamine donating reagents have also been described.
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Affiliation(s)
- Mohammad A. Alam
- Department of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, AR 72467, USA
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17
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Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. Eur J Med Chem 2018; 150:9-29. [DOI: 10.1016/j.ejmech.2018.02.065] [Citation(s) in RCA: 175] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 02/13/2018] [Accepted: 02/20/2018] [Indexed: 12/25/2022]
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18
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Abdelkarim H, Neelarapu R, Madriaga A, Vaidya AS, Kastrati I, Wang YT, Taha TY, Thatcher GRJ, Frasor J, Petukhov PA. Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Amine-based Histone Deacetylase Inhibitors. ChemMedChem 2017; 12:2030-2043. [PMID: 29080240 PMCID: PMC5881582 DOI: 10.1002/cmdc.201700449] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/19/2017] [Indexed: 01/08/2023]
Abstract
Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-aminoheptanohydroxamic acid-based HDAC inhibitors. Introduction of an amino group with one or two surface binding groups (SBGs) yielded a successful strategy to develop novel and potent HDAC inhibitors. The secondary amines were found to be generally more potent than the corresponding tertiary amines. Docking studies suggested that the SBGs of tertiary amines cannot be favorably accommodated at the gorge region of the binding site. The secondary amines with naphthalen-2-ylmethyl, 5-phenylthiophen-2-ylmethyl, and 1H-indol-2-ylmethyl (2 j) substituents exhibited the highest potency against class I HDACs: HDAC1 IC50 39-61 nm, HDAC2 IC50 260-690 nm, HDAC3 IC50 25-68 nm, and HDAC8 IC50 320-620 nm. The cytotoxicity of a representative set of secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors against HT-29, SH-SY5Y, and MCF-7 cancer cells correlated with their inhibition of HDAC1, 2, and 3 and was found to be similar to or better than that of suberoylanilide hydroxamic acid (SAHA). Compounds in this series increased the acetylation of histones H3 and H4 in a time-dependent manner. DMPK studies indicated that secondary amine 2 j is metabolically stable and has plasma and brain concentrations >23- and >1.6-fold higher than the IC50 value for class I HDACs, respectively. Overall, the secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors exhibit excellent lead- and drug-like properties and therapeutic capacity for cancer applications.
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Affiliation(s)
- Hazem Abdelkarim
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Raghupathi Neelarapu
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Antonett Madriaga
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Aditya S. Vaidya
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Irida Kastrati
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Yue-ting Wang
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Taha Y. Taha
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Gregory R. J. Thatcher
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
| | - Jonna Frasor
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Pavel A. Petukhov
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
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19
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Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients. J Hum Genet 2016; 61:823-30. [PMID: 27251006 DOI: 10.1038/jhg.2016.61] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 04/25/2016] [Accepted: 05/06/2016] [Indexed: 01/14/2023]
Abstract
Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.
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20
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Chen Y, Wang X, Xiang W, He L, Tang M, Wang F, Wang T, Yang Z, Yi Y, Wang H, Niu T, Zheng L, Lei L, Li X, Song H, Chen L. Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities. J Med Chem 2016; 59:5488-504. [PMID: 27186676 DOI: 10.1021/acs.jmedchem.6b00579] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
In the present study, a series of novel histone deacetylase (HDAC) inhibitors using the morpholinopurine as the capping group were designed and synthesized. Several compounds demonstrated significant HDAC inhibitory activities and antiproliferative effects against diverse human tumor cell lines. Among them, compound 10o was identified as a potent class I and class IIb HDAC inhibitor with good pharmaceutical profile and druglike properties. Western blot analysis further confirmed that 10o more effectively increased acetylated histone H3 than panobinostat (LBH-589) and vorinostat (SAHA) at the same concentration in vitro. In in vivo efficacy evaluations of HCT116, MV4-11, Ramos, and MM1S xenograft models, 10o showed higher efficacy than SAHA or LBH-589 without causing significant loss of body weight and toxicity. All the results indicated that 10o could be a suitable candidate for treatment of both solid and hematological cancer.
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Affiliation(s)
- Yong Chen
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.,School of Chemical Engineering, Sichuan University , Chengdu, 610065, China
| | - Xiaoyan Wang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Wei Xiang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Lin He
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Minghai Tang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Fang Wang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Taijin Wang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Zhuang Yang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Yuyao Yi
- Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Hairong Wang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Ting Niu
- Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Li Zheng
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Lei Lei
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Xiaobin Li
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
| | - Hang Song
- School of Chemical Engineering, Sichuan University , Chengdu, 610065, China
| | - Lijuan Chen
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China
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21
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Xiao Z, Morris-Natschke SL, Lee KH. Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates. Med Res Rev 2016; 36:32-91. [PMID: 26359649 PMCID: PMC4679534 DOI: 10.1002/med.21377] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bioisosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.
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Affiliation(s)
- Zhiyan Xiao
- Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Susan L. Morris-Natschke
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA
| | - Kuo-Hsiung Lee
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA
- Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
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22
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Ganai SA. Strategy for enhancing the therapeutic efficacy of histone deacetylase inhibitor dacinostat: the novel paradigm to tackle monotonous cancer chemoresistance. Arch Pharm Res 2015:10.1007/s12272-015-0673-9. [PMID: 26481010 DOI: 10.1007/s12272-015-0673-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/13/2015] [Indexed: 01/01/2023]
Abstract
Histone deacetylases (HDACs) regulate gene expression by creating the closed state of chromatin via histone hypoacetylation. Histone acetylation deregulation caused by aberrant expression of classical HDACs leads to imprecise gene regulation culminating in various diseases including cancer. Histone deacetylase inhibitors (HDACi), the small-molecules modulating the biological function of HDACs have shown promising results in inducing cell cycle arrest, differentiation and apoptosis in tumour models. HDACi do not show desired cytotoxic effect when used in monotherapy due to triggering of various resistance mechanisms in cancer cells emphasizing the desperate need of novel strategies that can be used to overcome such challenges. The present article provides intricate details about the novel HDACi dacinostat (LAQ-824) against multiple myeloma and acute myeloid leukaemia. The distinct molecular mechanisms modulated by dacinostat in exerting cytotoxic effect against the defined malignancies have also been detailed. The article also explains the strategy that can be used to circumvent the conventional therapy resistant cases and for enhancing the therapeutic efficacy of dacinostat for effective anticancer therapy.
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Affiliation(s)
- Shabir Ahmad Ganai
- Plant Virology and Molecular Pathology Laboratory, Division of Plant Pathology, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Srinagar, 190025, India.
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23
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Gohain M, Lin S, Bezuidenhoudt BC. Al(OTf)3-catalyzed SN2′ substitution of the β-hydroxy group in Morita–Baylis–Hillman adducts with indoles. Tetrahedron Lett 2015. [DOI: 10.1016/j.tetlet.2015.03.131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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24
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Pharmacophore modelling, validation, 3D virtual screening, docking, design and in silico ADMET simulation study of histone deacetylase class-1 inhibitors. Med Chem Res 2014. [DOI: 10.1007/s00044-014-1057-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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25
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Butler MS, Robertson AAB, Cooper MA. Natural product and natural product derived drugs in clinical trials. Nat Prod Rep 2014; 31:1612-61. [DOI: 10.1039/c4np00064a] [Citation(s) in RCA: 383] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The 25 Natural Product (NP)-derived drugs launched since 2008 and the 100 NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) in clinical trials or in registration at the end of 2013 are reviewed.
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Affiliation(s)
- Mark S. Butler
- Division of Chemistry and Structural Biology
- Institute for Molecular Bioscience
- The University of Queensland
- Brisbane, Australia
| | - Avril A. B. Robertson
- Division of Chemistry and Structural Biology
- Institute for Molecular Bioscience
- The University of Queensland
- Brisbane, Australia
| | - Matthew A. Cooper
- Division of Chemistry and Structural Biology
- Institute for Molecular Bioscience
- The University of Queensland
- Brisbane, Australia
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26
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Feng T, Wang H, Su H, Lu H, Yu L, Zhang X, Sun H, You Q. Novel N-hydroxyfurylacrylamide-based histone deacetylase (HDAC) inhibitors with branched CAP group (Part 2). Bioorg Med Chem 2013; 21:5339-54. [DOI: 10.1016/j.bmc.2013.06.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 06/05/2013] [Accepted: 06/06/2013] [Indexed: 01/16/2023]
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27
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Grassadonia A, Cioffi P, Simiele F, Iezzi L, Zilli M, Natoli C. Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies. Cancers (Basel) 2013; 5:919-42. [PMID: 24202327 PMCID: PMC3795372 DOI: 10.3390/cancers5030919] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/03/2013] [Accepted: 07/12/2013] [Indexed: 02/06/2023] Open
Abstract
Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms.
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Affiliation(s)
- Antonino Grassadonia
- Department of Experimental and Clinical Sciences, University ’G. d’Annunzio’, I-66013 Chieti, Italy; E-Mail:
| | - Pasquale Cioffi
- Hospital Pharmacy, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (P.C.); (F.S.)
| | - Felice Simiele
- Hospital Pharmacy, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (P.C.); (F.S.)
| | - Laura Iezzi
- Oncology Department, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (L.I.); (M.Z.)
| | - Marinella Zilli
- Oncology Department, “SS. Annunziata” Hospital, I-66013 Chieti, Italy; E-Mails: (L.I.); (M.Z.)
| | - Clara Natoli
- Department of Experimental and Clinical Sciences, University ’G. d’Annunzio’, I-66013 Chieti, Italy; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-0871-355-6708; Fax: +39-0871-355-6732
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28
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Gopalan B, Ponpandian T, Kachhadia V, Bharathimohan K, Vignesh R, Sivasudar V, Narayanan S, Mandar B, Praveen R, Saranya N, Rajagopal S, Rajagopal S. Discovery of adamantane based highly potent HDAC inhibitors. Bioorg Med Chem Lett 2013; 23:2532-7. [PMID: 23538115 DOI: 10.1016/j.bmcl.2013.03.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 02/25/2013] [Accepted: 03/01/2013] [Indexed: 01/04/2023]
Abstract
Herein, we report the development of highly potent HDAC inhibitors for the treatment of cancer. A series of adamantane and nor-adamantane based HDAC inhibitors were designed, synthesized and screened for the inhibitory activity of HDAC. A number of compounds exhibited GI50 of 10-100 nM in human HCT116, NCI-H460 and U251 cancer cells, in vitro. Compound 32 displays efficacy in human tumour animal xenograft model.
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Affiliation(s)
- Balasubramanian Gopalan
- Drug Discovery Research Centre, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India
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29
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Histone deacetylase inhibitors in the treatment for multiple myeloma. Int J Hematol 2013; 97:324-32. [DOI: 10.1007/s12185-013-1290-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 02/06/2013] [Indexed: 10/27/2022]
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30
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Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives. Future Med Chem 2012; 4:1439-60. [PMID: 22857533 DOI: 10.4155/fmc.12.80] [Citation(s) in RCA: 135] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Histone deacetylase inhibitors (HDACis) are one of the last frontiers in pharmaceutical research. Several classes of HDACi have been identified. Although more than 20 HDACi are under preclinical and clinical investigation as single agents and in combination therapies against different cancers, just two of them were approved by the US FDA: Zolinza(®) and Istodax(®), both licensed for the treatment of cutaneous T-cell lymphoma, the latter also of peripheral T-cell lymphoma. Since HDAC enzymes act by forming multiprotein complexes (clusters), containing cofactors, the main problem in designing new HDACi is that the inhibition activity evaluated on isolated enzyme isoforms does not match the in vivo outcomes. In the coming years, the research will be oriented toward a better understanding of the functioning of these protein complexes as well as the development of new screening assays, with the final goal to obtain new drug candidates for the treatment of cancer.
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Abstract
Suberoylanilide hydroxamic acid (vorinostat) was the first of the histone deacetylase inhibitors (HDACi) to be entered as therapy for the treatment of cutaneous T-cell lymphoma. Since then, a number of HDACi belonging to the short-chain fatty acid, hydroxamate, cyclic peptide or benzamide classes have been investigated in Phase II or III clinical trials (alone or in combination) for the treatment of many kinds of tumors. In addition, HDACi can be useful in antimalarial and antifungal therapies, and can reactivate HIV-1 expression in latent cellular reservoirs, thus suggesting that they could be used in combination with highly active antiretroviral therapy. Moreover, they have also proved their efficacy in neurodegenerative diseases, such as Huntington's disease, Parkinson's disease and Friedreich's ataxia. In particular, a new series of bis-anilides demonstrating a peculiar mechanism of action displayed highly beneficial effects against Huntington's disease and Friedreich's ataxia. In addition, a number of sirtuin inhibitors demonstrated antiproliferative effects in cell assays as well as in mouse tumor models, thus suggesting a role of such compounds in therapy against cancer. Furthermore, the SIRT2-selective AGK-2 has been reported to have protective effects against Parkinson's disease, and resveratrol and other sirtuin activators can be useful for the treatment of Alzheimer's disease.
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Affiliation(s)
- Antonello Mai
- Pasteur Institute-Cenci Bolognetti Foundation, Drug Chemistry and Technologies Department, University of Rome Sapienza, Piazzale Aldo Moro 5, Rome, Italy.
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32
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Shultz M, Fan J, Chen C, Cho YS, Davis N, Bickford S, Buteau K, Cao X, Holmqvist M, Hsu M, Jiang L, Liu G, Lu Q, Patel C, Suresh JR, Selvaraj M, Urban L, Wang P, Yan-Neale Y, Whitehead L, Zhang H, Zhou L, Atadja P. The design, synthesis and structure-activity relationships of novel isoindoline-based histone deacetylase inhibitors. Bioorg Med Chem Lett 2011; 21:4909-12. [PMID: 21742496 DOI: 10.1016/j.bmcl.2011.06.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 06/02/2011] [Accepted: 06/06/2011] [Indexed: 12/20/2022]
Abstract
The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization.
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Affiliation(s)
- Michael Shultz
- Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
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33
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Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney JD, Holmqvist M, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao YM, Zhou L, Atadja P. Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. J Med Chem 2011; 54:4752-72. [PMID: 21650221 DOI: 10.1021/jm200388e] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.
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Affiliation(s)
- Michael D Shultz
- Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139, United States.
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34
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Wang H, Yu N, Chen D, Lee KCL, Lye PL, Chang JWW, Deng W, Ng MCY, Lu T, Khoo ML, Poulsen A, Sangthongpitag K, Wu X, Hu C, Goh KC, Wang X, Fang L, Goh KL, Khng HH, Goh SK, Yeo P, Liu X, Bonday Z, Wood JM, Dymock BW, Kantharaj E, Sun ET. Discovery of (2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile. J Med Chem 2011; 54:4694-720. [PMID: 21634430 DOI: 10.1021/jm2003552] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.
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Affiliation(s)
- Haishan Wang
- Chemistry Discovery, S*BIO Pte Ltd., The Capricorn, Singapore Science Park II, Singapore, Singapore.
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35
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Design and synthesis of aryl ether and sulfone hydroxamic acids as potent histone deacetylase (HDAC) inhibitors. Bioorg Med Chem Lett 2011; 21:324-8. [DOI: 10.1016/j.bmcl.2010.11.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Revised: 10/29/2010] [Accepted: 11/01/2010] [Indexed: 01/03/2023]
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36
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Identification of four potential epigenetic modulators from the NCI structural diversity library using a cell-based assay. J Biomed Biotechnol 2010; 2011:868095. [PMID: 21234371 PMCID: PMC3014726 DOI: 10.1155/2011/868095] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 10/07/2010] [Indexed: 11/17/2022] Open
Abstract
Epigenetic pathways help control the expression of genes. In cancer and other diseases, aberrant silencing or overexpression of genes, such as those that control cell growth, can greatly contribute to pathogenesis. Access to these genes by the transcriptional machinery is largely mediated by chemical modifications of DNA or histones, which are controlled by epigenetic enzymes, making these enzymes attractive targets for drug discovery. Here we describe the characterization of a locus derepression assay, a fluorescence-based mammalian cellular system which was used to screen the NCI structural diversity library for novel epigenetic modulators using an automated imaging platform. Four structurally unique compounds were uncovered that, when further investigated, showed distinct activities. These compounds block the viability of lung cancer and melanoma cells, prevent cell cycle progression, and/or inhibit histone deacetylase activity, altering levels of cellular histone acetylation.
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37
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Chen L, Petrelli R, Gao G, Wilson DJ, McLean GT, Jayaram HN, Sham YY, Pankiewicz KW. Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure. Bioorg Med Chem 2010; 18:5950-64. [PMID: 20650640 DOI: 10.1016/j.bmc.2010.06.081] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Revised: 06/19/2010] [Accepted: 06/23/2010] [Indexed: 11/17/2022]
Abstract
Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.
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Affiliation(s)
- Liqiang Chen
- Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
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38
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Kiyokawa S, Hirata Y, Nagaoka Y, Shibano M, Taniguchi M, Yasuda M, Baba K, Uesato S. New orally bioavailable 2-aminobenzamide-type histone deacetylase inhibitor possessing a (2-hydroxyethyl)(4-(thiophen-2-yl)benzyl)amino group. Bioorg Med Chem 2010; 18:3925-33. [PMID: 20452226 DOI: 10.1016/j.bmc.2010.04.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 04/12/2010] [Accepted: 04/13/2010] [Indexed: 11/26/2022]
Abstract
New 2-aminobenzamide-type histone deacetylase (HDAC) inhibitors were synthesized. They feature a sulfur-containing bicyclic arylmethyl moiety-a surface recognition domain introduced to increase in cellular uptake-and a substituted tert-amino group which affects physicochemical properties such as aqueous solubility. Compound 22 with a (2-hydroxyethyl)(4-(thiophen-2-yl)benzyl)amino group reduced the volume of human colon cancer HCT116 xenografts in nude mice to T/C 67% by oral administration at 45mg/kg, which was comparable to the rate (T/C 62%) for a positive control, MS-275. Western blot analyses as well as cell cycle and TUNEL assays by flow cytometry suggested that the two compounds inhibited the growth of cancer cells via similar mechanisms.
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Affiliation(s)
- Shingo Kiyokawa
- Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan
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39
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Efficient Lewis acid-assisted Brønsted acid (LBA) catalysis in the iron-catalyzed Friedel-Crafts alkylation reaction of indoles. OPEN CHEM 2010. [DOI: 10.2478/s11532-010-0016-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AbstractLewis acid-assisted Brønsted acid (LBA) catalysis was proposed for the iron-catalyzed Friedel-Crafts alkylation of indoles with chalcones. This proposal was supported by the ESI-MS and cyclic voltammetry. The addition of acac to the iron-catalyzed Friedel-Crafts alkylation of indoles with chalcones created a powerful catalytic system, which makes the alkylation reactions occur easily under mild conditions.
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40
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Pontiki E, Hadjipavlou-Litina D. Histone deacetylase inhibitors (HDACIs). Structure--activity relationships: history and new QSAR perspectives. Med Res Rev 2010; 32:1-165. [PMID: 20162725 DOI: 10.1002/med.20200] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. HDAC inhibitors (HDACIs) block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumor cells. In this article, a survey of published quantitative structure-activity relationships (QSARs) studies are presented and discussed in the hope of identifying the structural determinants for anticancer activity. Secondly a two-dimensional QSAR study was carried out on biological results derived from various types of HDACIs and from different assays using the C-QSAR program of Biobyte. The QSAR analysis presented here is an attempt to organize the knowledge on the HDACIs with the purpose of designing new chemical entities with enhanced inhibitory potencies and to study the mechanism of action of the compounds. This study revealed that lipophilicity is one of the most important determinants of activity. Additionally, steric factors such as the overall molar refractivity (CMR), molar volume (MgVol), the substituent's molar refractivity (MR) (linear or parabola), or the sterimol parameters B(1) and L are important. Electronic parameters indicated as σ(p), are found to be present only in one case.
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Affiliation(s)
- Eleni Pontiki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece.
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41
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Cang S, Ma Y, Liu D. New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer. J Hematol Oncol 2009; 2:22. [PMID: 19486511 PMCID: PMC2695818 DOI: 10.1186/1756-8722-2-22] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Accepted: 06/01/2009] [Indexed: 02/08/2023] Open
Abstract
DNA methylation and histone acetylation are two well known epigenetic chromatin modifications. Epigenetic agents leading to DNA hypomethylation and histone hyperacetylation have been approved for treatment of hematological disorders. The first histone deacetylase inhibitor, vorinostat, has been licensed for cutaneous T cell lymphoma treatment. More than 11 new epigenetic agents are in various stages of clinical development for therapy of multiple cancer types. In this review we summarize novel histone deacetylase inhibitors and new regimens from clinical trials for epigenetic therapy of cancer.
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Affiliation(s)
- Shundong Cang
- Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA
- Henan Province People's Hospital, Zhengzhou, PR China
| | - Yuehua Ma
- Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA
- Henan Province People's Hospital, Zhengzhou, PR China
| | - Delong Liu
- Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA
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42
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Mahboobi S, Dove S, Sellmer A, Winkler M, Eichhorn E, Pongratz H, Ciossek T, Baer T, Maier T, Beckers T. Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rbeta, and histone deacetylases. J Med Chem 2009; 52:2265-79. [PMID: 19301902 DOI: 10.1021/jm800988r] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability. Combinations of HDAC inhibitors with the kinase inhibitor 1 (Imatinib) in recent studies showed additive and synergistic effects. Here we present a new concept by combining inhibition of protein kinases and HDACs, two independent pharmacological activities, in one synthetic small molecule. In general, the HDAC inhibition profile, the potencies, and the probable binding modes to HDAC1 and HDAC6 were similar as for 6 (SAHA). Inhibition of Abl kinase in biochemical assays was maintained for most compounds, but in general the kinase selectivity profile differed from that of 1 with nearly equipotent inhibition of the wild-type and the Imatinib resistant Abl T(315)I mutant. A potent cellular inhibition of PDGFR and cytotoxicity toward EOL-1 cells, a model for idiopathic hypereosinophilic syndrome (HES), are restored or enhanced for selected analogues (12b, 14b, and 18b). Cytotoxicity was evaluated by using a broad panel of tumor cell lines, with selected analogues displaying mean IC(50) values between 3.6 and 7.1 muM.
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Affiliation(s)
- Siavosh Mahboobi
- Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
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43
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Epigenetic therapies in haematological malignancies: searching for true targets. Eur J Cancer 2009; 45:1137-1145. [PMID: 19346125 DOI: 10.1016/j.ejca.2009.03.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Accepted: 03/03/2009] [Indexed: 01/23/2023]
Abstract
Epigenetic alterations complement genetic mutations as a molecular mechanism leading to cell transformation, and maintenance of the cancer phenotype. Of note, they are reversible by pharmacological manipulation of the enzymes responsible for chromatin modification: indeed, epigenetic drugs (histone deacetylase inhibitors and DNA demethylating agents) are currently on the market, inducing proliferative arrest and death of tumor cells. These drugs, however, have been effective only in a few tumor types: the lack of consistent clinical results is mainly due to their use in a poorly targeted approach, since the epigenetic alterations present in cancer cells are mostly unknown. In a few cases (notably, leukemias expressing RAR and MLL fusion proteins), the molecular mechanisms underlying tumor-selective and tumor-specific epigenetic alterations have started to be deciphered. These studies are revealing a dazzling complexity in the mechanisms leading to alterations of the epigenome, and the need of combination therapies targeting different chromatin modifiers to reach an effective reversion of epigenetic alterations.
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44
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YU L, LIU F, CHEN Y, YOU Q. Pharmacophore Identification of Hydroxamate HDAC 1 Inhibitors. CHINESE J CHEM 2009. [DOI: 10.1002/cjoc.200990091] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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45
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Lawless MW, Norris S, O'Byrne KJ, Gray SG. Targeting histone deacetylases for the treatment of disease. J Cell Mol Med 2008; 13:826-52. [PMID: 19175682 PMCID: PMC3823402 DOI: 10.1111/j.1582-4934.2008.00571.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The ‘histone code’ is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular ‘code’ recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.
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Affiliation(s)
- M W Lawless
- Centre for Liver Disease, School of Medicine and Medical Science, Mater Misericordiae University Hospital - University College Dublin, Dublin, Ireland
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46
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Nelson ER, Habibi HR. Functional significance of a truncated thyroid receptor subtype lacking a hormone-binding domain in goldfish. Endocrinology 2008; 149:4702-9. [PMID: 18511506 DOI: 10.1210/en.2008-0107] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Thyroid hormones are important mediators of growth and development in vertebrates and act by binding to a specific family of thyroid receptors (TRs). The TRs belong to the nuclear receptor superfamily, with two conserved regions, a DNA binding domain and a ligand binding domain (LBD). We recently demonstrated the presence of four TR subtypes in goldfish, two with complete DNA binding domains and LBDs (TRalpha-1 and TRbeta) and two novel forms including a transcript resembling TRalpha with variation in the LBD as well as a TRalpha-truncated (TRalpha-t) form lacking a LBD. To study the functional significance of TR subtypes, we first investigated the regulation of hepatic goldfish deiodinase type 3 (D3) by T3 and validated a bioassay in which D3 gene expression is up-regulated significantly in vivo and in vitro. Using short interfering RNA, TRalpha-1, TRbeta, or TRalpha-t was specifically knocked down and thyroid hormone-induced D3 gene expression was measured. Short interfering RNA against TRalpha-1 or TRbeta reduced the T3 induction of deiodinase gene expression to 50% or less than 25% of control (T3 treated) cells, respectively. Knocking down TRalpha-t alone, however, increased D3 expression 500-fold supporting the hypothesis that TRalpha-t plays a modulatory role in thyroid hormone-induced gene expression. Our results provide important insight into thyroid receptor biology in goldfish and a framework for the better understanding of thyroid receptor function in all vertebrates.
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MESH Headings
- Animals
- Cells, Cultured
- Cloning, Molecular
- Codon, Nonsense/genetics
- Female
- Gene Expression Regulation, Enzymologic/drug effects
- Goldfish/genetics
- Goldfish/metabolism
- Goldfish/physiology
- Histone Deacetylases/physiology
- Iodide Peroxidase/genetics
- Male
- Protein Isoforms/chemistry
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- Protein Isoforms/physiology
- Protein Structure, Tertiary/genetics
- Protein Structure, Tertiary/physiology
- Receptors, Thyroid Hormone/chemistry
- Receptors, Thyroid Hormone/genetics
- Receptors, Thyroid Hormone/metabolism
- Receptors, Thyroid Hormone/physiology
- Triiodothyronine/metabolism
- Triiodothyronine/pharmacology
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Affiliation(s)
- Erik R Nelson
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4
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47
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Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead. Int J Biochem Cell Biol 2008; 41:199-213. [PMID: 18790076 DOI: 10.1016/j.biocel.2008.08.020] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 08/08/2008] [Accepted: 08/08/2008] [Indexed: 12/16/2022]
Abstract
In addition to genetic events, a variety of epigenetic events have been widely reported to contribute to the onset of many diseases including cancer. DNA methylation and histone modifications (such as acetylation, methylation, sumoylation, and phosphorylation) involving chromatin remodelling are among the most studied epigenetic mechanisms for regulation of gene expression leading, when altered, to some diseases. Epigenetic therapy tries to reverse the aberrations followed to the disruption of the balance of the epigenetic signalling ways through the use of both natural compounds and synthetic molecules, active on specific epi-targets. Such epi-drugs are, for example, inhibitors of DNA methyltransferases, histone deacetylases, histone acetyltransferases, histone methyltransferases, and histone demethylases. In this review we will focus on the chemical aspects of such molecules, joined to their effective (or potential) application in cancer therapy.
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48
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Haefner M, Bluethner T, Niederhagen M, Moebius C, Wittekind C, Mossner J, Caca K, Wiedmann M. Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors. World J Gastroenterol 2008; 14:3681-92. [PMID: 18595135 PMCID: PMC2719231 DOI: 10.3748/wjg.14.3681] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer.
METHODS: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1, acH4, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1.
RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In vivo, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.
CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.
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49
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Butler MS. Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 2008; 25:475-516. [PMID: 18497896 DOI: 10.1039/b514294f] [Citation(s) in RCA: 524] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Natural product and natural product-derived compounds that are being evaluated in clinical trials or are in registration (as at 31st December 2007) have been reviewed, as well as natural product-derived compounds for which clinical trials have been halted or discontinued since 2005. Also discussed are natural product-derived drugs launched since 2005, new natural product templates and late-stage development candidates.
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Affiliation(s)
- Mark S Butler
- MerLion Pharmaceuticals, 1 Science Park Road, The Capricorn 05-01, Singapore Science Park II, Singapore 117528.
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Andrews DM, Stokes ES, Carr GR, Matusiak ZS, Roberts CA, Waring MJ, Brady MC, Chresta CM, East SJ. Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors. Bioorg Med Chem Lett 2008; 18:2580-4. [DOI: 10.1016/j.bmcl.2008.03.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2008] [Revised: 03/13/2008] [Accepted: 03/14/2008] [Indexed: 10/22/2022]
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