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Current Drug Discovery Technologies

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ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

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Review Article

Discovery and Development of HDAC Inhibitors: Approaches for the Treatment of Cancer a Mini-review

Author(s): Roshani Patel*, Arjun Modi and Hitesh Vekariya

Volume 21, Issue 6, 2024

Published on: 23 February, 2024

Article ID: e230224227378 Pages: 16

DOI: 10.2174/0115701638286941240217102948

Price: $65

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Abstract

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin-4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid-capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Keywords: Histone deacetylase inhibitors, IC50 (μM), cancer cells, acetylation, DNA, transcriptional machinery.

Graphical Abstract

[1]
Kouzarides T. Chromatin modifications and their function. Cell 2007; 128(4): 693-705.
[http://dx.doi.org/10.1016/j.cell.2007.02.005] [PMID: 17320507]
[2]
Marks PA, Xu WS, Pascual-Leone A. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med 2019; 25(1): 600-8.
[3]
Pao PC, Tsai LH. Histone deacetylases 1 and 2 in memory function. ACS Chem Neurosci 2022; 13(7): 848-58.
[http://dx.doi.org/10.1021/acschemneuro.1c00775] [PMID: 35263084]
[4]
Seto E, Yoshida M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb Perspect Biol 2014; 6(4): a018713.
[http://dx.doi.org/10.1101/cshperspect.a018713] [PMID: 24691964]
[5]
Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 hindsight. J Med Chem 2020; 63(21): 12460-84.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00830] [PMID: 32608981]
[6]
Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 2014; 13(9): 673-91.
[http://dx.doi.org/10.1038/nrd4360] [PMID: 25131830]
[7]
Fedele P, Orlando L, Cinieri S. Targeting triple negative breast cancer with histone deacetylase inhibitors. Expert Opin Investig Drugs 2017; 26(11): 1199-206.
[http://dx.doi.org/10.1080/13543784.2017.1386172] [PMID: 28952409]
[8]
Cao LL, Song X, Pei L, Liu L, Wang H, Jia M. Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer. Medicine 2017; 96(31): e7663.
[http://dx.doi.org/10.1097/MD.0000000000007663] [PMID: 28767587]
[9]
Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 2009; 32(11): 591-601.
[http://dx.doi.org/10.1016/j.tins.2009.06.002] [PMID: 19775759]
[10]
Wei DG, Chiang V, Fyne E, et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog 2014; 10(4): e1004071.
[http://dx.doi.org/10.1371/journal.ppat.1004071] [PMID: 24722454]
[11]
Chun P. Therapeutic effects of histone deacetylase inhibitors on kidney disease. Arch Pharm Res 2018; 41(2): 162-83.
[http://dx.doi.org/10.1007/s12272-017-0998-7] [PMID: 29230688]
[12]
Das Gupta K, Shakespear MR, Iyer A, Fairlie DP, Sweet MJ. Histone deacetylases in monocyte/macrophage development, activation and metabolism: Refining HDAC targets for inflammatory and infectious diseases. Clin Transl Immunology 2016; 5(1): e62.
[http://dx.doi.org/10.1038/cti.2015.46] [PMID: 26900475]
[13]
Yoon S, Eom GH. HDAC and HDAC inhibitor: From cancer to cardiovascular diseases. Chonnam Med J 2016; 52(1): 1-11.
[http://dx.doi.org/10.4068/cmj.2016.52.1.1] [PMID: 26865995]
[14]
Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 2007; 25(1): 84-90.
[http://dx.doi.org/10.1038/nbt1272] [PMID: 17211407]
[15]
Mann BS, Bolen CR. HDAC inhibitors for the treatment of cancer. J Cell Physiol 2019; 234(6): 8491-505.
[16]
Göttlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20(24): 6969-78.
[http://dx.doi.org/10.1093/emboj/20.24.6969] [PMID: 11742974]
[17]
Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5(9): 769-84.
[http://dx.doi.org/10.1038/nrd2133] [PMID: 16955068]
[18]
Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6(1): 38-51.
[http://dx.doi.org/10.1038/nrc1779] [PMID: 16397526]
[19]
Patnaik A, Rowinsky EK, Villalona MA, et al. A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies. Clin Cancer Res 2002; 8(7): 2142-8.
[PMID: 12114414]
[20]
Gojo I, Jiemjit A, Trepel JB, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 2007; 109(7): 2781-90.
[http://dx.doi.org/10.1182/blood-2006-05-021873] [PMID: 17179232]
[21]
Fan W, Zhang L, Wang X, Jia H, Zhang L. Discovery of potent histone deacetylase inhibitors with modified phenanthridine caps. J Enzyme Inhib Med Chem 2021; 36(1): 707-18.
[http://dx.doi.org/10.1080/14756366.2021.1892089] [PMID: 33663315]
[22]
Zhang JH, Mottamal M, Jin HS, et al. Design, synthesis and evaluation of belinostat analogs as histone deacetylase inhibitors. Future Med Chem 2019; 11(21): 2765-78.
[http://dx.doi.org/10.4155/fmc-2018-0587] [PMID: 31702394]
[23]
Al-Sanea MM, Gotina L, Mohamed MF, et al. Design, synthesis and biological evaluation of new HDAC1 and HDAC2 inhibitors endowed with ligustrazine as a novel cap moiety. Drug Des Devel Ther 2020; 14: 497-508.
[http://dx.doi.org/10.2147/DDDT.S237957] [PMID: 32103894]
[24]
Thakur A, Tawa GJ, Henderson MJ, et al. Design, synthesis, and biological evaluation of quinazolin-4-one-based hydroxamic acids as dual PI3K/HDAC inhibitors. J Med Chem 2020; 63(8): 4256-92.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00193] [PMID: 32212730]
[25]
Liang T, Hou X, Zhou Y, Yang X, Fang H. Design, synthesis, and biological evaluation of 2,4-imidazolinedione derivatives as HDAC6 isoform-selective inhibitors. ACS Med Chem Lett 2019; 10(8): 1122-7.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00084] [PMID: 31413795]
[26]
Chen J, Li D, Li W, et al. Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors. Bioorg Med Chem 2018; 26(14): 3958-66.
[http://dx.doi.org/10.1016/j.bmc.2018.06.016] [PMID: 29954683]
[27]
Yang F, Zhao N, Song J, et al. Design, synthesis and biological evaluation of novel coumarin-based hydroxamate derivatives as histone deacetylase (HDAC) inhibitors with antitumor activities. Molecules 2019; 24(14): 2569.
[http://dx.doi.org/10.3390/molecules24142569] [PMID: 31311163]
[28]
Taha TY, Aboukhatwa SM, Knopp RC, et al. Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based histone deacetylase 8 selective inhibitors. ACS Med Chem Lett 2017; 8(8): 824-9.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00126] [PMID: 28835796]
[29]
Chen X, Zhao S, Wu Y, Chen Y, Lu T, Zhu Y. Design, synthesis and biological evaluation of 2-amino-N-(2-aminophenyl)thiazole-5-carboxamide derivatives as novel Bcr-Abl and histone deacetylase dual inhibitors. RSC Advances 2016; 6(105): 103178-84.
[http://dx.doi.org/10.1039/C6RA21271A]
[30]
Kim JH, Ali KH, Oh YJ, Seo YH. Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group. Medicine 2022; 101(17): e29049.
[http://dx.doi.org/10.1097/MD.0000000000029049] [PMID: 35512065]
[31]
Reßing N, Marquardt V, Gertzen CGW, et al. Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity. MedChemComm 2019; 10(7): 1109-15.
[http://dx.doi.org/10.1039/C8MD00454D] [PMID: 31391882]
[32]
Yao D, Li C, Jiang J, et al. Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer. Eur J Med Chem 2020; 205(112648): 112648.
[http://dx.doi.org/10.1016/j.ejmech.2020.112648] [PMID: 32791401]
[33]
He J, Wang S, Liu X, et al. Synthesis and biological evaluation of HDAC inhibitors with a novel zinc binding group. Front Chem 2020; 8(256): 256.
[http://dx.doi.org/10.3389/fchem.2020.00256] [PMID: 32351936]
[34]
Myeong AC, SunYou P, HyeYun C, Yoojin S. Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes. Sci Rep 2019; 9(13187): 1-12.
[35]
Yuan G, Jilong D, Xiawen D, et al. Design, synthesis and biological evaluation of novel histone deacetylase (HDAC) inhibitors derived from β-elemene scaffold. J Enzyme Inhib Med Chem 2023; 38(1): 1-22.
[PMID: 36305251]

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