0
Views
0
CrossRef citations to date
0
Altmetric
Review Article

A patent review of histone deacetylase 8 (HDAC8) inhibitors (2013-present)

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Received 31 Mar 2024, Accepted 08 Aug 2024, Accepted author version posted online: 09 Aug 2024
Accepted author version

REFERENCES

  • Misztak P, Pańczyszyn-Trzewik P, Sowa-Kućma M. Histone deacetylases (HDACs) as therapeutic target for depressive disorders. Pharmacol Rep. 2018;70(2):398–408. doi: 10.1016/j.pharep.2017.08.001
  • Chen QW, Zhu XY, Li YY, et al. Epigenetic regulation and cancer (review). Oncol Rep. 2014;31(2):523–532. doi: 10.3892/or.2013.2913
  • Biswas S, Rao CM Epigenetics in cancer: Fundamentals and Beyond. Pharmacol Ther. 2017;173:118–134. doi:10.1016/j.pharmthera.2017.02.011
  • Adhikari N, Jha T, Ghosh B. Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy. J. Med. Chem. 2021;64(13):8827–8869. doi:10.1021/acs.jmedchem.0c01676
  • Banerjee S, Adhikari N, Amin SA, et al. Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview. Eur. J. Med. Chem. 2019;164:214–240. doi:10.1016/j.ejmech.2018.12.039
  • Müller MM, Muir TW. Histones: at the crossroads of peptide and protein chemistry. Chem. Rev. 2015;115(6):2296–2349. doi:10.1021/cr5003529
  • Chakrabarti A, Oehme I, Witt O, et al. HDAC8: a multifaceted target for therapeutic interventions. Trends Pharmacol. Sci. 2015;36(7):481–492. doi:10.1016/j.tips.2015.04.013
  • Roche J, Bertrand P. Inside HDACs with more selective HDAC inhibitors. Eur. J. Med. Chem. 2016;121:451–483. doi:10.1016/j.ejmech.2016.05.047
  • Rajaraman S, Balakrishnan R, Deshmukh D, et al. HDAC8 as an emerging target in drug discovery with special emphasis on medicinal chemistry. Future Med Chem. 2023;15(10):885–908. doi: 10.4155/fmc-2023-0054
  • Amin SA, Adhikari N, Jha T Is dual inhibition of metalloenzymes HDAC-8 and MMP-2 a potential pharmacological target to combat hematological malignancies?. Pharmacol Res. 2017;122:8–19. doi:10.1016/j.phrs.2017.05.002
  • Chakrabarti A, Melesina J, Kolbinger FR, et al. Targeting histone deacetylase 8 as a therapeutic approach to cancer and neurodegenerative diseases. Future Med. Chem. 2016;8(13):1609–1634. doi:10.4155/fmc-2016-0117
  • Nian H, Bisson WH, Dashwood WM, et al. Alpha-keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells. Carcinogenesis. 2009;30(8):1416–1423. doi: 10.1093/carcin/bgp147
  • Kim JY, Cho H, Jung Yoo J, et al. HDAC8 Deacetylates HIF-1α and enhances its protein stability to promote tumor growth and migration in melanoma. Cancers (Basel). 2023; 15(4):1123. doi: 10.3390/cancers15041123.
  • Olson DE, deshi ND, Wolfson NA, et al. An unbiased approach to identify endogenous substrates of “histone” deacetylase 8. ACS Chem Biol. 2014; 9(10):2210–2216. doi: 10.1021/cb500492r.
  • Tang X, Li L, Su F, et al. HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration. Nucleic Acids Res. 2020; 48(6): 2912–2923. doi: 10.1093/nar/gkaa039.
  • Adhikari N, Amin SA, Jha T. Selective and nonselective HDAC8 inhibitors: a therapeutic patent review. Pharm Pat Anal. 2018;7(6):259–276. doi: 10.4155/ppa-2018-0019
  • Marek M, Shaik TB, Heimburg T, et al. Characterization of histone deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants. J Med Chem. 2018;61(22):10000–10016. doi: 10.1021/acs.jmedchem.8b01087
  • https://www.rcsb.org/
  • Amin SA, Adhikari N, Jha T. Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery. Future Med Chem. 2017; 9(18):2211–2237. doi: 10.4155/fmc-2017-0130.
  • Stenzel K, Hamacher A, Hansen FK, et. al. Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines. J Med Chem. 2017; 60(13):5334–5348. doi: 10.1021/acs.jmedchem.6b01538.
  • Mwakwari SC, Patil V, Guerrant W, et al. Macrocyclic histone deacetylase inhibitors. Curr Top Med Chem. 2010;10(14):1423–1440. doi: 10.2174/156802610792232079
  • Fontana A, Cursaro I, Carullo G, et al. A therapeutic perspective of HDAC8 in different diseases: an overview of selective inhibitors. Int J Mol Sci. 2022;23(17):10014. doi: 10.3390/ijms231710014
  • Kim JY, Cho H, Yoo J, et al. Pathological Role of HDAC8: Cancer and Beyond. Cells. 2022; 11(19):3161. doi: 10.3390/cells11193161.
  • Chen J, Cao L, Ma J, et al. HDAC8 promotes liver metastasis of colorectal cancer via inhibitionof irf1 and upregulation of SUCNR1. Oxid. Med. Cell Longev. 2022, 2815187 (2022).
  • Menbari MN, Rahimi K, Ahmadi A, et al. Association of HDAC8 expression with pathological findings in triple negative and non-triple negative breast cancer: implications for diagnosis. Iran Biomed. J. 24(5), 288–294 (2020).
  • Li Y, Liang R, Sun M, et al. AMPK-dependent phosphorylation of HDAC8 triggers PGM1 expression to promote lung cancer cell survival under glucose starvation. Cancer Lett. 2020;478:82–92. doi: 10.1016/j.canlet.2020.03.007
  • Kim JY, Han SY, Yoo J, et al. HDAC8-selective inhibition by PCI-34051 enhances the anticancer effects of ACY-241 in ovarian cancer cells. Int. J. Mol. Sci. 23(15), 8645 (2022).
  • Vanaja GR, Ramulu HG, Kalle AM. Overexpressed HDAC8 in cervical cancer cells shows functional redundancy of tubulin deacetylation with HDAC6. Cell Commun. Signal. 16(1), 20 (2018).
  • Mahajan M, Suryavanshi S, Bhowmick S, et al. Matairesinol, an active constituent of HC9 polyherbal formulation, exhibits HDAC8 inhibitory and anticancer activity. Biophys. Chem. 273, 106588 (2021).
  • Song S, Wang Y, Xu P, et al. The inhibition of histone deacetylase 8 suppresses proliferation and inhibits apoptosis in gastric adenocarcinoma. Int. J. Oncol. 47(5), 1819–1828 (2015).
  • Zhang M, Ying JB, Wang SS, et al. Exploring the binding mechanism of HDAC8 selective inhibitors: Lessons from the modification of cap group. J. Cell Biochem. 121(5–6), 3162–3172 (2020).
  • Kang Y, Nian H, Rajendran P, et al. HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Cell Death Dis. 2014;5(10):e1476. doi: 10.1038/cddis.2014.422
  • Oehme I, Deubzer HE, Lodrini M, et al. Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert Opin Investig Drugs. 2009;18(11):1605–1617. doi:10.1517/14728220903241658
  • Lehmann M, Hoffmann MJ, Koch A, et al. Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment. J Exp Clin Cancer Res. 2014;33(1):59. doi:10.1186/s13046-014-0059-8
  • Ahn MY, Yoon JH. Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma. Oncol Rep. 2017;37(1):540–546. doi:10.3892/or.2016.5280
  • Santos-Barriopedro I, Li Y, Bahl S, et al. HDAC8 affects MGMT levels in glioblastoma cell lines via interaction with the proteasome receptor ADRM1. Genes Cancer. 2019;10(5–6):119–133. doi:10.18632/genesandcancer.197
  • Lopez G, Bill KL, Bid HK, et al. HDAC8, a potential therapeutic target for the treatment of malignant peripheral nerve sheath tumors (MPNST). PLoS One. 10(7), e0133302 (2015).
  • Tian Y, Wong VW, Wong GL, et al. Histone deacetylase HDAC8 promotes insulin resistance and β-catenin activation in NAFLD-associated hepatocellular carcinoma. Cancer Res. 75(22), 4803–4816 (2015).
  • Watters JM, Wright G, Smith MA, Shah B, Wright KL. Histone deacetylase 8 inhibition suppresses mantle cell lymphoma viability while preserving natural killer cell function. Biochem. Biophys. Res. Commun. 534, 773–779 (2021).
  • Balasubramanian S, Ramos J, Luo W, et al. A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia. 2008;22(5):1026–1034. doi:10.1038/leu.2008.9
  • Spreafico M, Gruszka AM, Valli D, et al. HDAC8: a promising therapeutic target for acute myeloid leukemia. Front. Cell Dev. Biol. 8, 844 (2020).
  • Zhang P, Brinton LT, Williams K, et al. Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition. Clin. Cancer Res. 27(8), 2352–2366 (2021).
  • Qi J, Singh S, Hua WK, et al. HDAC8 inhibition specifically targets Inv(16) acute myeloid leukemic stem cells by restoring p53 acetylation. Cell Stem Cell. 2015;17(5):597–610. doi: 10.1016/j.stem.2015.08.004
  • Yoon JI, Cho H, Jeon R, et al. Therapeutic efficacy of novel HDAC inhibitors SPA3052 and SPA3074 against intestinal inflammation in a murine model of colitis. Pharmaceuticals (Basel). 2022;15(12):1515. doi:10.3390/ph15121515
  • Zhou X, Chen H, Shi Y, et al. Histone deacetylase 8 inhibition prevents the progression of peritoneal fibrosis by counteracting the epithelial-mesenchymal transition and blockade of M2 macrophage polarization. Front. Immunol. 14, 1137332 (2023).
  • Saito S, Zhuang Y, Suzuki T, et al. HDAC8 inhibition ameliorates pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 316(1), L175–L186 (2019).
  • Spreafico M, Cafora M, Bragato C, et al. Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy. Pharmacol Res. 2021;170:105750. doi: 10.1016/j.phrs.2021.105750
  • Xiao T, Fu Y, Zhu W, et al. HDAC8, a potential therapeutic target, Regulates proliferation and differentiation of bone marrow stromal cells in fibrous dysplasia. Stem. Cells Transl. Med. 8(2), 148–161 (2019).
  • Deardorff MA, Porter NJ, Christianson DW. Structural aspects of HDAC8 mechanism and dysfunction in cornelia de lange syndrome spectrum disorders. Protein Sci. 2016;25(11):1965–1976. doi:10.1002/pro.3030
  • Mio C, Passon N, Fogolari F, et al. A novel de novo HDAC8 missense mutation causing Cornelia de Lange syndrome. Mol. Genet. Genomic. Med. 9(9), e1612 (2021).
  • Lee CH, Choi Y, Cho H, et al. Histone deacetylase 8 inhibition alleviates cholestatic liver injury and fibrosis. Biochem. Pharmacol. 183, 114312 (2021).
  • Zhang Y, Zou J, Tolbert E, et al. Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis. Faseb J. 2020;34(6):7295–7310. doi:10.1096/fj.201903254R
  • Marek M, Kannan S, Hauser AT, et al. Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke schistosoma mansoni. PloS Pathog. 2013;9(9):e1003645. doi: 10.1371/journal.ppat.1003645
  • Noce B, Di Bello E, Zwergel C, et al. Chemically diverse S. mansoni HDAC8 inhibitors reduce viability in worm larval and adult stages. ChemMedchem. 2023;18(3):e202200510. doi: 10.1002/cmdc.202200510
  • Xia B, Lu J, Wang R, Yang Z, Zhou X, Huang P. miR-21-3p regulates influenza a virus replication by targeting histone deacetylase-8. Front. Cell Infect. Microbiol. 8, 175 (2018).
  • Chen Y, Pan C, Lu Y, et al. HDAC8 drives spindle organization during meiotic maturation of porcine oocytes. Cell Prolif. 2021;54(10):e13119. doi:10.1111/cpr.13119
  • Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 insight and Hindsight. J Med Chem. 2020;63(21):12460–12484. doi: 10.1021/acs.jmedchem.0c00830
  • ClinicalTrials.gov. [accessed 2024 Mar 31]. Available from: https://clinicaltrials.gov
  • The J. David Gladstone Institutes, Ithaca College. Inhibitors for hdac8. 2008: WO2008101186A1
  • Shandong University. Tyrosine derivative histone deacetylases inhibitor and application thereof. 2010; CN101723896
  • S*Bio Pte Ltd. Biaryl linked hydroxamates: preparation and pharmaceutical applications. 2005; WO2005040161A1
  • Sookmyung Women’s University Industry-Academic Cooperation Foundation. Novel binary histone deacetylase inhibitor and pharmaceutical composition containing same. 2022; WO2023177249A1.
  • Forma Therapeutics, Inc. [6,6] fused bicyclic hdac8 inhibitors. 2017; WO2017040963A1
  • Shandong University, Histone deacetylase 8 selective depressant and its preparation method and application. 2018; CN108299255A.
  • Institute of Chemical Industry of Forest Products of CAF. Synthesis method of methylene ether urushiol hydroxamic acid derivative with HDAC (Histone-like oxidase) inhibitory activity. 2019; CN110256398B.
  • Institute of Chemical Industry of Forest Products of CAF. Synthesis method of novel urushiol-based hydroxamic acid derivatives having HDAC (Histone deacetylase) inhibition and antitumor activity. 2020; CN111440138A
  • Institute of Chemical Industry of Forest Products of CAF. Urushiol-based hydroxamic acid HDAC inhibitor with targeted antitumor activity and preparation method and application thereof. 2023; CN116375698B.
  • Pharmacyclics LLC. Indole derivatives as inhibitors of histone deacetylase. 2016; US9371281.
  • Pharmacyclics LLC. Uses of selective inhibitors of hdac8 and treatment of inflammatory conditions. 2015; US20150038542A1.
  • Stomatological Hospital of Nanjing Medical University. Application of the HDAC8 inhibitor in the drug of preparation treatment fibrous dysplasia. 2019; CN110420208A.
  • Pharmacyclics LLC. Selective inhibitors of histone deacetylase. 2016; EP2265590B1.
  • Pharmacyclics, Inc. Cinnamic acid hydroxyamides as inhibitors of histone deacetylase 8. 2013, WO2013101600A1.
  • Nagoya City University. Hydroxamic acid derivative and HDAC8 inhibitor using the same. 2015; JP5725475B2.
  • Kyoto Prefectural Public Univ Corp, Nagoya City University, Tak Circulator Co Ltd. Hydroxamic acid derivatives and hdac8 inhibitors. 2016; JP2016017040A.
  • Hainan Research Institute Of Zhejiang University. HDAC8 inhibitor and preparation method and application thereof. 2023; CN117430565.
  • Forma Therapeutics Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors. 2017; US9745253B2.
  • Boston University, Dana Farber Cancer Institute Inc. Selective histone deacetylase 8 inhibitors. 2018; US10087149B2.
  • Valo Health Inc. [6,6] fused bicyclic HDAC8 inhibitors. 2022; US11414392B2.
  • Academia Sinica, Taipei Medical University TMU, City of Hope. HDAC8 inhibitors for treating cancer. 2019; US10308596B2.
  • Incyte Corp. Heterocyclic compounds and uses thereof. 2020; US10723705B2.
  • Broad Institute Inc. Cycloalkenyl hydroxamic acid derivatives and their use as histone deacetylase inhibitors. 2020; US10793538B2.
  • Council of Scientific and Industrial Research CSIR. Indole (sulfomyl) n-hydroxy benzamide derivatives as selective HDAC inhibitors. 2021; US11072583B2.
  • Wayne State University. Structural requirements of histone deacetylase inhibitors: C4-modified saha analogs display dual HDAC6/HDAC8 selectivity. 2018; US20180057448A1.
  • Shenzhen University. Selective histone deacetylase 8 degrader, preparation method and application thereof in anti-tumor activity. 2023; WO2023151113A1.
  • Daegu Gyeongbuk Advanced Medical Industry Promotion Foundation. 3,4-dihydroquinoxaline-2-carboximide derivative compound and pharmaceutical composition comprising same for preventing or treating cancer disease. 2023; WO2023191379A1.
  • Kan Saila Co Ltd. It can be used as the bicycle hydroxamic acid compound of the inhibitor of mammal histone deacetylase activity. 2018; CN108602812A.
  • Sookmyung Women’s University Industry-Academic Cooperation Foundation. Novel Compounds, preparation method thereof, and pharmaceutical composition for use in preventing or treating Neuroblastoma containing the same as an active ingredient. 2019; KR20190087799A.
  • Cava Healthcare Inc. Compounds for increasing mhc-i expression and modulating histone deacetylase activity. 2022; US20220105051A1.
  • Klotho Therapeutics, Inc. Novel heterocyclic compounds and related methods of manufacture and use in hdac inhibition. 2022; WO2022178544A1.
  • Kyushu University NUC. Histone deacetylation enzyme inhibitor, food (health supplement) or medicine, bittering agent, and drug using this inhibitor, and production methods thereof. 2018; JP2018104396A.
  • Universidade de de Aveiro. Nitro-containing compounds, compositions and uses thereof. 2024; EP4306106A1.
  • Hochschule Darmstadt. Selective hdac8 inhibitors and their uses. 2018; US20180311257A1.
  • University Of Connecticut. Substituted tropolone derivatives and methods of use. 2013; WO2013192554A1.
  • Banerjee S, Baidya SK, Adhikari N, Jha T. A comparative quantitative structural assessment of benzothiazine-derived HDAC8 inhibitors by predictive ligand-based drug designing approaches. SAR QSAR Environ. Res. 2022;33(12):987–1011. doi:10.1080/1062936X.2022.2155241
  • Banerjee S, Amin SA, Adhikari N, Jha T. Essential elements regulating HDAC8 inhibition: a classification based structural analysis and enzyme-inhibitor interaction study of hydroxamate based HDAC8 inhibitors. J. Biomol. Struct. Dyn. 2020;38(18):5513–5525. doi:10.1080/07391102.2019.1704881
  • Banerjee S, Adhikari N, Amin SA, et al. Structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi-QSAR modeling study. J Biomol Struct Dyn. 2020;38(5):1551–1564. doi: 10.1080/07391102.2019.1617782
  • Wolff B, Jänsch N, Sugiarto WO, et al. Synthesis and structure activity relationship of 1, 3-benzo-thiazine-2-thiones as selective HDAC8 inhibitors. Eur J Med Chem. 2019 Dec 15;184:111756. doi: 10.1016/j.ejmech.2019.111756.
  • Muth M, Jänsch N, Kopranovic A, et al. Covalent inhibition of histone deacetylase 8 by 3,4-dihydro-2H-pyrimido[1,2-c][1,3]benzothiazin-6-imine. Biochim Biophys Acta Gen Subj. 2019;1863(3):577–585. doi: 10.1016/j.bbagen.2019.01.001.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.