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Review

Histone deacetylase (HDAC) inhibitors in cancer: a patent review (2017-present)

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Pages 263-274 | Received 25 Nov 2019, Accepted 31 Jan 2020, Published online: 05 Feb 2020

References

  • Yoshida M, Kudo N, Kosono S, et al. Chemical and structural biology of protein lysine deacetylases. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(5):297–321.
  • Zagni C, Floresta G, Monciino G, et al. The search for potent, small-molecule HDACIs in cancer treatment: a decade after vorinostat. Med Res Rev. 2017 Nov;37(6):1373–1428.
  • Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014 Sept;13(9):673–691.
  • Zwergel C, Stazi G, Valente S, et al. histone deacetylase inhibitors: updated studies in various epigenetic-related diseases. J Clin Epigenet. 2016;2:1–7.
  • Porter NJ, Osko JD, Diedrich D, et al. Histone deacetylase 6-selective inhibitors and the influence of capping groups on hydroxamate-zinc denticity. J Med Chem. 2018 Sept 13;61(17):8054–8060.
  • West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014 Jan;124(1):30–39.
  • Heimburg T, Kolbinger FR, Zeyen P, et al. Structure-based design and biological characterization of selective histone deacetylase 8 (HDAC8) inhibitors with anti-neuroblastoma activity. J Med Chem. 2017 Dec 28;60(24):10188–10204.
  • Zhao C, Zang J, Ding Q, et al. Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors. Eur J Med Chem. 2018 Apr 25;150:282–291.
  • Parra M. Class IIa HDACs – new insights into their functions in physiology and pathology. Febs J. 2015 May;282(9):1736–1744.
  • Li T, Zhang C, Hassan S, et al. Histone deacetylase 6 in cancer. J Hematol Oncol. 2018 Sept 3;11(1):111.
  • Yue L, Sharma V, Horvat NP, et al. HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms. Blood. 2020;135(3):191–207.
  • Thomas A, Miller DJW, Belvedere S. Histone deacetylase inhibitors. J Med Chem. 2003;46(24):5097–5116.
  • Marson CM. Histone deacetylase inhibitors: design, structure-activity relationships and therapeutic implications for cancer. Anticancer Agents Med Chem. 2009;9:661–692.
  • Luan Y, Li J, Bernatchez JA, et al. Histone deacetylase hybrid inhibitors for cancer therapy. J Med Chem. 2019 Apr 11;62(7):3171–3183.
  • Guha M. HDAC inhibitors still need a home run, despite recent approval. Nat Rev Drug Discov. 2015 Apr;14(4):225–226.
  • Rosik L, Niegisch G, Fischer U, et al. Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells. Cancer Biol Ther. 2014 June 1;15(6):742–757.
  • Zeng H, Qu J, Jin N, et al. Feedback activation of leukemia inhibitory factor receptor limits response to histone deacetylase inhibitors in breast cancer. Cancer Cell. 2016 Sept 12;30(3):459–473.
  • Cao F, Zwinderman MRH, Dekker FJ. The process and strategy for developing selective histone deacetylase 3 inhibitors. Molecules. 2018. 2. 23(3):Mar.
  • McClure JJ, Zhang C, Inks ES, et al. Development of Allosteric Hydrazide-Containing class I histone deacetylase inhibitors for use in acute myeloid leukemia. J Med Chem. 2016 Nov 10;59(21):9942–9959.
  • Li X, Peterson YK, Inks ES, et al. Class I HDAC inhibitors display different antitumor mechanism in leukemia and prostatic cancer cells depending on their p53 status. J Med Chem. 2018 Mar 22;61(6):2589–2603.
  • Kozlov MV, Konduktorov KA, Shcherbakova AS, et al. Synthesis of N’-propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs) and evaluation of their impact on activities of HDACs and replication of hepatitis C virus (HCV). Bioorg Med Chem Lett. 2019 Aug 15;29(16):2369–2374.
  • Bressi JC, Jennings AJ, Skene R, et al. Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett. 2010 May 15;20(10):3142–3145.
  • 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 Nov 21;61(22):10000–10016.
  • Evrot E, Ebel N, Romanet V, et al. JAK1/2 and Pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease. Clin Cancer Res. 2013 Nov 15;19(22):6230–6241.
  • Rahmani M, Aust MM, Benson EC, et al. PI3K/mTOR inhibition markedly potentiates HDAC inhibitor activity in NHL cells through BIM- and MCL-1-dependent mechanisms in vitro and in vivo. Clin Cancer Res. 2014 Sept 15;20(18):4849–4860.
  • Huang JM, Sheard MA, Ji L, et al. Combination of vorinostat and flavopiridol is selectively cytotoxic to multidrug-resistant neuroblastoma cell lines with mutant TP53. Mol Cancer Ther. 2010 Dec;9(12):3289–3301.
  • Booth L, Roberts JL, Sander C, et al. The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo. Oncotarget. 2017 Mar 7;8(10):16367–16386.
  • Tavallai S, Hamed HA, Grant S, et al. Pazopanib and HDAC inhibitors interact to kill sarcoma cells. Cancer Biol Ther. 2014 May;15(5):578–585.
  • Wang J, Pursell NW, Samson ME, et al. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther. 2013 June;12(6):925–936.
  • Hesham HM, Lasheen DS, Abouzid KAM. Chimeric HDAC inhibitors: comprehensive review on the HDAC-based strategies developed to combat cancer. Med Res Rev. 2018 Sept;38(6):2058–2109.
  • Zhang K, Lai F, Lin S, et al. Design, synthesis, and biological evaluation of 4-methyl quinazoline derivatives as anticancer agents simultaneously targeting phosphoinositide 3-kinases and histone deacetylases. J Med Chem. 2019 Aug 8;62(15):6992–7014.
  • Zang J, Liang X, Huang Y, et al. Discovery of novel pazopanib-based HDAC and VEGFR dual inhibitors targeting cancer epigenetics and angiogenesis simultaneously. J Med Chem. 2018 June 28;61(12):5304–5322.
  • Yao L, Mustafa N, Tan EC, et al. Design and synthesis of ligand efficient dual inhibitors of janus kinase (JAK) and histone deacetylase (HDAC) based on ruxolitinib and vorinostat. J Med Chem. 2017 Oct 26;60(20):8336–8357.
  • Yang EG, Mustafa N, Tan EC, et al. Design and synthesis of janus kinase 2 (JAK2) and histone deacetlyase (HDAC) bispecific inhibitors based on pacritinib and evidence of dual pathway inhibition in hematological cell lines. J Med Chem. 2016 Sept 22;59(18):8233–8262.
  • Liang X, Zang J, Li X, et al. Discovery of novel janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors for the treatment of hematological malignancies. J Med Chem. 2019 Apr 25;62(8):3898–3923.
  • Li Y, Luo X, Guo Q, et al. Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a novel inhibitor targeting cyclin-dependent kinase 4/9 (CDK4/9) and histone deacetlyase1 (HDAC1) against malignant cancer. J Med Chem. 2018 Apr 12;61(7):3166–3192.
  • Huang Y, Dong G, Li H, et al. Discovery of Janus kinase 2 (JAK2) and histone deacetylase (HDAC) dual inhibitors as a novel strategy for the combinational treatment of leukemia and invasive fungal infections. J Med Chem. 2018 July 26;61(14):6056–6074.
  • To KKW, Fu LW. CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance. Invest New Drugs. 2018 Feb;36(1):10–19.
  • Chu-Farseeva YY, Mustafa N, Poulsen A, et al. Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat. Eur J Med Chem. 2018 Oct 5;158:593–619.
  • Lu D, Yan J, Wang L, et al. Design, synthesis, and biological evaluation of the first c-Met/HDAC inhibitors based on pyridazinone derivatives. ACS Med Chem Lett. 2017 Aug 10;8(8):830–834.
  • Haiching M, Feng Y. Quinoline and isoquinoline based HDAC inhibitors and methods of use thereof. WO2019169267 (A1). 2019.
  • Van Duzer John H, Ralph M. Piperazine derivatives as selective HDAC1, 2 inhibitors. WO2018098296 (A1). 2018.
  • Chen C, Hsieh H. HDAC3-selective inhibitors. WO2018223122 (A1). 2018.
  • Nathan F, John. L. Bicyclic inhibitors of histone deacetylase. WO2018132531 (A1). 2018.
  • Chen X, Luan Y, Han. Y. Emodin derivative with HDAC inhibitory activity and preparation method and application of emodin derivative. CN107176912 A. 2017.
  • Zhang Y, Wenfang X JZ. Pazopanib-based HDAC and VEGFR double-target inhibitor, preparation method therefor and application thereof. WO2019029295 (A1). 2019.
  • Sheng C, Baoli L, Dong G. NAMPT/HDAC dual-target inhibitor and preparation method thereof. CN106916101 (A). 2017.
  • Cai J, Congcong L, Min J., et al. BET (bromodomain and extraterminal domain)/HDAC (histone deacetylase) double-target inhibitor, and preparation method and application thereof. CN107033147 (A). 2017.
  • Jin L, Bo W, Zhang D. HDAC inhibitor as well as preparation method and application thereof. CN109705071 (A). 2019.
  • Zheng X, Yee Pui NG, Mary-magaret Z 2-spiro-5-and 6-hydroxamic acid indanes as HDAC inhibitors. WO2017218950 (A1). 2017.
  • Liu D, Linxiang Zhao XQ. Hydroxamic acid compound having HDAC6 inhibitory activity and application thereof. CN109574936 (A). 2019.
  • Zheng X, Pui Yee NG, Thomason Jennifer R. [6,6] Fused bicyclic HDAC8 inhibitors. WO2017040963 (A1). 2017.
  • Sridharan R, Hallur Mahanandeesha S, Purushottam D. Cyclopropyl-amide compounds as dual LSD1/HDAC inhibitors. CN109153636 (A). 2019.
  • Barbara V, Caprini Gianluca GF. Selective HDAC6 inhibitors. WO2018189340 (A1). 2018.
  • Hao W, Changqing Wei GQ. HDAC6 selective inhibitors, preparation method therefor, and appilcation thereof. WO2018130155 (A1). 2018.
  • Siavosh M, Pongratz Herwig EG. Novel HDAC6 inhibitors, with improved solubility and their uses. WO2019007836 (A1). 2019.
  • Alan K, Sida S, Joel. B. Tetrahydraquinoline substituted hydroxamic acids as selective histone deacetylase 6 inhibitors. WO2017142883 (A1). 2017.
  • Gaisina Irina AK. NRF and HIF activators/HDAC inhibitors and therapeutic methods using the same. WO2018200608 (A1). 2018.
  • Liu Z, Wang X, Liu. P. Histone deacetylase HDAC6 inhibitor, and preparation method and application thereof. CN109020921 (A). 2018.
  • Yuan Q, Xie R, Deng B. HDAC (histone deacetylase) inhibiting agent, and preparation method and purpose thereof. CN107011238 (A). 2017.
  • Han S, Kim Y, Hong. J HAD C N- novel hydroxamic acids or N-hydroxybenzamides incorporating quinazoline as histone deacetylase inhibitors and anticancer composition comprising the same. KR102000035 (B1). 2019.
  • Pflum MK. Structural requirements of histone deacetylase inhibitors: C4-modified saha analogs display dual HDAC6/HDAC8 selectivity. US2018057448 (A1). 2018.
  • William DB, Guorong YE, JongYoung Y. JAK and HDAC dual-inhibitor compounds. WO2017196261 (A1). 2017.
  • Zhang Y, Liang X, Jak WX. (Janus kinase) and HDAC (histone deacetylase) double-target-spot inhibitor with 4-aminopyrazole structure, and preparation method and application thereof. CN108864057 (A). 2018.
  • Zhang H, Shifeng Liu YX. Heterocyclic compound as SYK inhibitor and/or SYK-HDAC dual inhibitor. WO2018108083 (A1). 2018.
  • Jing X, Chengqing Ning HH. MDM2-HDAC double-target inhibitor, medicinal composition and preparation and application of MDM2-HDAC double-target inhibitor. CN108864113 (A). 2018.
  • Xiang R, Yan Fan LY. Novel heterocyclic derivative with CDK (cyclin-dependent kinase) 4/6 and HDAC (histone deacetylase) inhibitory activities. CN106831780 (A). 2017.
  • Meng X, Siju B, Zhou Z. Glycolylurea and glycolythiourea compound with Ar (androgen receptor) and HDAC (histone deacetylase) double inhibition and application thereof. CN109796437 (A). 2019.
  • Cheng Y, Mahmun HM, Douglas S. Novel HDAC inhibitors and methods of treatment using the same. WO2017039726 (A1). 2017.
  • Zigang L, Yin F, Wang. D. Stable polypeptide inhibitor targeting HDAC and application of stable polypeptide inhibitor. CN109912686 (A). 2019.
  • Abbas W, Richard B, Al SC. 3-Aryl and heteroaryl substituted 5-trifluoromethyl oxadiazoles as histone deacetylase (HDAC6) inhibitors. WO2017222951 (A1). 2017.
  • Abbas W, Berger Richard ASC. 3-heteroaryl substituted 5-trifluoromethyl oxadiazoles as histone deacetylase (HDAC6) inhibitors. WO2017222952 (A1). 2017.
  • Faria Freitas M, Cuendet M, Bertrand P. MCPB. HDAC inhibitors: a2013–2017 patent survey. Expert Opin Ther Pat. 2018;28(5):365–381.
  • Shen S, Kozikowski AP. Why hydroxamates may not be the best histone deacetylase inhibitors–what some may have forgotten or would rather forget? ChemMedChem. 2016 Jan 5;11(1):15–21.
  • Porter NJ, Mahendran A, Breslow R, et al. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13459–13464.
  • Bresciani A, Ontoria JM, Biancofiore I, et al. Improved selective class I HDAC and novel selective HDAC3 inhibitors: beyond hydroxamic acids and benzamides. ACS Med Chem Lett. 2019 Apr 11;10(4):481–486.
  • Senger J, Melesina J, Marek M, et al. Synthesis and biological investigation of oxazole hydroxamates as highly selective histone deacetylase 6 (HDAC6) inhibitors. J Med Chem. 2016 Feb 25;59(4):1545–1555.
  • Osko JD, Porter NJ, Narayana Reddy PA, et al. Exploring structural determinants of inhibitor affinity and selectivity in complexes with Histone Deacetylase 6. J Med Chem. 2020 Jan 9;63(1):295–308.
  • Shen S, Kozikowski AP. A patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2014–2019). Expert Opin Ther Pat. 2020 Feb;30(2):121–136.
  • 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. 2020 Jan 7.DOI: 10.1002/jcb.29583.
  • Fantin VR, Loboda A, Paweletz CP, et al. Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. Cancer Res. 2008 May 15;68(10):3785–3794.
  • Proschak E, Stark H, Merk D. Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J Med Chem. 2019 Jan 24;62(2):420–444.
  • Zhou J, Jiang X, He S, et al. Rational design of multitarget-directed ligands: strategies and emerging paradigms. J Med Chem. 2019 Oct 24;62(20):8881-914.
  • Woods DM, Sodre AL, Villagra A, et al. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 2015 Dec;3(12):1375–1385.
  • Terranova-Barberio M, Thomas S, Ali N, et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 2017;8(69):114156–114172.
  • Banik D, Moufarrij S, Villagra A. Immunoepigenetics combination therapies: an overview of the role of HDACs in cancer immunotherapy. Int J Mol Sci. 2019 May 7;20:9.
  • Festino L, Vanella V, Trojaniello C, et al. Selecting immuno-oncology-based drug combinations - what should we be considering? Expert Rev Clin Pharmacol. 2018 Oct;11(10):971–985.
  • Knox T, Sahakian E, Banik D, et al. Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. 2019 Apr 16;9(1):6136.
  • McCaw TR, Randall TD, Forero A, et al. Modulation of antitumor immunity with histone deacetylase inhibitors. Immunotherapy. 2017;9(16):1359–1372.
  • Bourguet E, Ozdarska K, Moroy G, et al. Class I HDAC inhibitors: potential new epigenetic therapeutics for alcohol use disorder (AUD). J Med Chem. 2018 Mar 8;61(5):1745–1766.
  • Rabal O, Sanchez-Arias JA, Cuadrado-Tejedor M, et al. Design, synthesis, and biological evaluation of first-in-class dual acting histone deacetylases (HDACs) and phosphodiesterase 5 (PDE5) Inhibitors for the treatment of alzheimer’s disease. J Med Chem. 2016 Oct 13;59(19):8967–9004.
  • Lee HY, Fan SJ, Huang FI, et al. 5-aroylindoles act as selective histone deacetylase 6 inhibitors ameliorating alzheimer’s disease phenotypes. J Med Chem. 2018 Aug 23;61(16):7087–7102.
  • Ziemka-Nalecz M, Jaworska J, Sypecka J, et al. Histone deacetylase inhibitors: a therapeutic key in neurological disorders? J Neuropathol Exp Neurol. 2018 Oct 1;77(10):855–870.
  • Hailu GS, Robaa D, Forgione M, et al. Lysine deacetylase inhibitors in parasites: past, present, and future perspectives. J Med Chem. 2017 June 22;60(12):4780–4804.

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