Novel Drugs Targeting the Epigenome

Abstract

Epigenetic drug discovery has its beginning in the cancer research arena, focusing first on DNA methylation and histone deacetylation. There are currently two DNA methyltransferase (DNMT) inhibitors and four histone deacetylase (HDAC) inhibitors approved by the US Food and Drug Administration (FDA) during the past 13 years. Over the past few years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms have exploded, providing new insights into the role of epigenetic control in gene regulation and leading to the discovery of a variety of new and specific drug targets. Among them, epigenetic “reader”—bromodomain and extra-terminal protein (BET), “writers”—disruptor of telomeric silencing 1-like (DOT1L), enhancer of zeste homolog 2 (EZH2), and protein arginine methyltransferase 5 (PRMT5), and “erasers”—lysine-specific histone demethylase 1 (LSD1) as well as isocitrate dehydrogenase (IDH) attract greater attention due to the ongoing clinical trials. This article provides a brief overview of new drugs modulating the above epigenetic targets, including their indication, mechanism of action, and disclosed chemical structures. The trend of epigenetic drug approval in the following few years is expectable, at least partially, from current clinical trials summarized in this review.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Abbreviations

AITL:

Angioimmunoblastic T-cell lymphoma

ALCL:

Anaplastic large cell lymphoma

AML:

Acute myeloid leukemia

ATRT:

Atypical teratoid rhabdoid tumor

BET:

Bromodomain and extra-terminal protein

BMS:

Bristol-Myers Squibb

BRD:

Bromodomain

CAD:

Coronary artery disease

CRPC:

Castration-resistant prostate cancer

CVD:

Cardiovascular disease

DLBCL:

Diffuse large B-cell lymphoma

DM:

Diabetes mellitus

DNMT:

DNA methyltransferase

DOT1L:

Disruptor of telomeric silencing 1-like

ER:

Estrogen receptor

EZH2:

Enhancer of zeste homolog 2

FDA:

Food and Drug Administration

GSK:

GlaxoSmithKline

HDAC:

Histone deacetylase

HMT:

Histone methyltransferase

IDH:

Isocitrate dehydrogenase

LSD1:

Lysine-specific histone demethylase 1

MCL:

Mantle cell lymphoma

MDS:

Myelodysplastic syndrome

MM:

Multiple myeloma

MRT:

Malignant rhabdoid tumor

NHL:

Non-Hodgkin lymphoma

NSCLC:

Non-small cell lung cancer

NMC:

NUT midline carcinoma

PRMT:

Protein arginine methyltransferase

RTK:

Rhabdoid tumors of the kidney

SCLC:

Small cell lung cancer

TNBC:

Triple-negative breast cancer

References

  1. 1.

    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8. doi:10.1016/j.cell.2007.02.006.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011;123(19):2145–56. doi:10.1161/CIRCULATIONAHA.110.956839.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Dawson MA. The cancer epigenome: concepts, challenges, and therapeutic opportunities. Science. 2017;355(6330):1147–52. doi:10.1126/science.aam7304.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630–41. doi:10.1038/nrg.2016.93.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    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. doi:10.1038/nrd4360.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Andreoli F, Barbosa AJ, Parenti MD, Del Rio A. Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. Curr Pharm Des. 2013;19(4):578–613.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Medina-Franco J. Epi-informatics: discovery and development of small molecule epigenetic drugs and probes. Oxford: Academic Press; 2016. p. 440.

  8. 8.

    Aparicio A, Weber JS. Review of the clinical experience with 5-azacytidine and 5-aza-2′-deoxycytidine in solid tumors. Curr Opin Investig Drugs. 2002;3(4):627–33.

    CAS  PubMed  Google Scholar 

  9. 9.

    Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 2012;21(3):430–46. doi:10.1016/j.ccr.2011.12.029.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Tsai HC, Baylin SB. Cancer epigenetics: linking basic biology to clinical medicine. Cell Res. 2011;21(3):502–17. doi:10.1038/cr.2011.24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Lee HZ, Kwitkowski VE, Del Valle PL, Ricci MS, Saber H, Habtemariam BA, et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res. 2015;21(12):2666–70. doi:10.1158/1078-0432.CCR-14-3119.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Garnock-Jones KP. Panobinostat: first global approval. Drugs. 2015;75(6):695–704. doi:10.1007/s40265-015-0388-8.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Mullard A. Chinese biopharma starts feeding the global pipeline. Nat Rev Drug Discov. 2017;16(7):443–6. doi:10.1038/nrd.2017.94.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov. 2012;11(5):384–400. doi:10.1038/nrd3674.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Morera L, Lubbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics. 2016;8:57. doi:10.1186/s13148-016-0223-4.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–73. doi:10.1038/nature09504.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Shapiro GI, Dowlati A, LoRusso PM, Eder JP, Anderson A, Do KT, et al. Abstract A49: clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). Mol Cancer Ther. 2015;14(12 Supplement 2):A49-A. doi:10.1158/1535-7163.targ-15-a49.

    Article  Google Scholar 

  18. 18.

    Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468(7327):1119–23. doi:10.1038/nature09589.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, et al. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem. 2013;56(19):7501–15. doi:10.1021/jm401088k.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I, Chaudhry MS, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014;123(5):697–705. doi:10.1182/blood-2013-01-478420.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Wyce A, Degenhardt Y, Bai YC, Le BC, Korenchuk S, Crouthamel MC, et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013;4(12):2419–29.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Berenguer-Daize C, Astorgues-Xerri L, Odore E, Cayol M, Cvitkovic E, Noel K, et al. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016;139(9):2047–55. doi:10.1002/ijc.30256.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Coude MM, Braun T, Berrou J, Dupont M, Bertrand S, Masse A, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-Myc in acute leukemia cells. Oncotarget. 2015;6(19):17698–712. doi:10.18632/oncotarget.4131.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Gaudio E, Tarantelli C, Ponzoni M, Odore E, Rezai K, Bernasconi E, et al. Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma. Oncotarget. 2016;7(36):58142–7. doi:10.18632/oncotarget.10983.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Boi M, Todaro M, Vurchio V, Yang SN, Moon J, Kwee I, et al. Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes. Oncotarget. 2016;7(48):79637–53. doi:10.18632/oncotarget.12876.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Stathis A, Zucca E, Bekradda M, Gomez-Roca C, Delord JP, de La Motte RT, et al. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov. 2016;6(5):492–500. doi:10.1158/2159-8290.CD-15-1335.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Vazquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, et al. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017;8(5):7598–613. doi:10.18632/oncotarget.13814.

    PubMed  Google Scholar 

  28. 28.

    Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Cote A, Leblanc Y, et al. Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials. J Med Chem. 2016;59(4):1330–9. doi:10.1021/acs.jmedchem.5b01882.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Siu KT, Ramachandran J, Yee AJ, Eda H, Santo L, O'Donnell EK, et al. Concomitant suppression of IKZF1, IRF4 and Myc contribute to the anti-tumor activity of the BET inhibitor, Cpi-0610, in disease models of multiple myeloma. Blood. 2016;128(22):3320.

    Google Scholar 

  30. 30.

    Siu KT, Eda H, Santo L, Ramachandran J, Koulnis M, Mertz J, et al. Effect of the BET inhibitor, Cpi-0610, alone and in combination with lenalidomide in multiple myeloma. Blood. 2015;126(23):4255.

    Google Scholar 

  31. 31.

    Millan DS, Morales MAA, Barr KJ, Cardillo D, Collis A, Dinsmore CJ, et al. FT-1101: a structurally distinct pan-BET bromodomain inhibitor with activity in preclinical models of hematologic malignancies. Blood. 2015;126(23):1367.

    Google Scholar 

  32. 32.

    Lejeune P, Sugawara T, Gelato KA, Ellinger-Ziegelbauer H, Fernandez-Montalvan AE, Schmees N et al. BAY 1238097, a novel BET inhibitor with strong efficacy in hematological tumor models. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 18-22, 2015. Cancer Res. 2015;75:3524. doi:10.1158/1538-7445.Am2015-3524.

  33. 33.

    Haendler B, Gelato KA, Schockel L, Sugawara T, Lejeune P, Ellinger-Ziegelbauer H et al. The BET inhibitor BAY 1238097 shows efficacy in BRAF wild-type and mutant melanoma models. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res. 2016;76: 4703. doi:10.1158/1538-7445.Am2016-4703.

  34. 34.

    Klingbeil O, Haendler B, Stresemann A, Merz C, Walter A, Fernandez-Montalvan AE et al. In vivo efficacy of BET inhibitor BAY 1238097 in preclinical models of melanoma and lung cancer. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res. 2016;76:4714. doi: 10.1158/1538-7445.Am2016-4714.

  35. 35.

    Liu PCC, Liu XM, Stubbs MC, Maduskuie T, Sparks R, Zolotarjova N et al. Discovery of a novel BET inhibitor INCB054329. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 18-22, 2015. Cancer Res. 2015;75:3523. doi:10.1158/1538-7445.Am2015-3523.

  36. 36.

    Stubbs M, Wen XM, Dostalik V, O'Connor S, Caulder E, Vogina A et al. Activity of the BET inhibitor INCB054329 in models of multiple myeloma. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 18-22, 2015. Cancer Res. 2015;75:691. doi:10.1158/1538-7445.Am2015-691.

  37. 37.

    Stubbs M, Collins R, Volgina A, Liu MK, Favata M, Rupar M et al. Activity of the BET inhibitor INCB054329 in models of lymphoma.  In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res. 2016;76:3780. doi: 10.1158/1538-7445.Am2016-3780.

  38. 38.

    Liu XS, Stubbs M, Ye M, Collins R, Favata M, Yang GJ et al. Combination of BET inhibitor INCB054329 and LSD1 inhibitor INCB059872 is synergistic for the treatment of AML in vitro and in vivo. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res. 2016;76:4702. doi:10.1158/1538-7445.Am2016-4702.

  39. 39.

    Stubbs MC, Liu XSM, Wen XM, Li J, Dostalik V, O'Connor S et al. The BET inhibitor INCB054329 is synergistic with JAK1 inhibition in models of multiple myeloma. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 18-22, 2015. Cancer Res. 2015;75:692. doi:10.1158/1538-7445.Am2015-692.

  40. 40.

    Liu XS, Li J, He X, Stubbs M, Favata M, Wen XM et al. The BET inhibitor INCB054329 is efficacious as a single agent or in combination with targeted agents in colorectal cancer models. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 18-22, 2015. Cancer Res. 2015;75:3525. doi:10.1158/1538-7445.Am2015-3525.

  41. 41.

    Koblish HK, Hansbury M, Hall L, Wang LC, Zhang Y, Covington M et al. The BET inhibitor INCB054329 enhances the activity of checkpoint modulation in syngeneic tumor models. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res. 2016;76:4904. doi:10.1158/1538-7445.Am2016-4904.

  42. 42.

    McDaniel K, Wang L, Sheppard G, Fidanze S, Pratt J, Liu DC et al. Functional group elaboration of a low molecular weight fragment to yield the novel BET family bromodomain inhibitor ABBV-075. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res. 2016;76:4695. doi:10.1158/1538-7445.Am2016-4695.

  43. 43.

    Bui MH, Lin X, Albert DH, Li L, Lam LT, Faivre EJ, et al. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Res. 2017;77(11):2976–89. doi:10.1158/0008-5472.CAN-16-1793.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Faivre EJ, Wilcox D, Lin X, Hessler P, Torrent M, He W, et al. Exploitation of castration-resistant prostate cancer transcription factor dependencies by the novel BET inhibitor ABBV-075. Mol Cancer Res. 2017;15(1):35–44. doi:10.1158/1541-7786.MCR-16-0221.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Bates J, Kusam S, Tannheimer S, Clarke A, Kenney T, Breckenridge D, et al. Combination of the BET inhibitor GS-5829 and a BCL2 inhibitor resulted in broader activity in DLBCL and MCL cell lines. Blood. 2016;128(22):5104.

    Google Scholar 

  46. 46.

    Bates J, Kusam S, Tannheimer S, Chan J, Li Y, Breckenridge D, et al. The combination of a BET inhibitor (GS-5829) and a BTK inhibitor (GS-4059) potentiates DLBCL cell line cell death and reduces expression of Myc, IL-10, and IL-6 in vitro. Blood. 2016;128(22):5116.

    Google Scholar 

  47. 47.

    Mead M, Von Euw E, Conklin D, Powell B, Manivong K, Do E, et al. Efficacy and mechanism of action of the novel bromodomain inhibitor, PLX51107, in B Cell malignancies. Blood. 2015;126(23):3702.

    Google Scholar 

  48. 48.

    Grieselhuber NR, Mitchell SR, Orwick S, Harrington BK, Goettl VM, Walker AR, et al. The novel BET inhibitor PLX51107 has in vitro and in vivo activity against acute myeloid leukemia. Blood. 2016;128(22):3941.

    Google Scholar 

  49. 49.

    Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S, Chatur S, et al. RVX-208 a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55(23):2580–9. doi:10.1016/j.jacc.2010.02.035.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Wasiak S, Gilham D, Tsujikawa LM, Halliday C, Calosing C, Jahagirdar R, et al. Downregulation of the complement cascade in vitro, in mice and in patients with cardiovascular disease by the BET protein inhibitor apabetalone (RVX-208). J Cardiovasc Transl Res. 2017; doi:10.1007/s12265-017-9755-z.

  51. 51.

    Perez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics. 2017;12(5):323–39. doi:10.1080/15592294.2016.1265710.

    Article  PubMed  Google Scholar 

  52. 52.

    Min J, Feng Q, Li Z, Zhang Y, Xu RM. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell. 2003;112(5):711–23.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Chang MJ, Wu HY, Achille NJ, Reisenauer MR, Chou CW, Zeleznik-Le NJ, et al. Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes. Cancer Res. 2010;70(24):10234–42. doi:10.1158/0008-5472.Can-10-3294.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20(1):53–65. doi:10.1016/j.ccr.2011.06.009.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122(6):1017–25. doi:10.1182/blood-2013-04-497644.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Justin N, Zhang Y, Tarricone C, Martin SR, Chen S, Underwood E, et al. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nat Commun. 2016;7:11316. doi:10.1038/ncomms11316.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Wassef M, Michaud A, Margueron R. Association between EZH2 expression, silencing of tumor suppressors and disease outcome in solid tumors. Cell Cycle. 2016;15(17):2256–62. doi:10.1080/15384101.2016.1208872.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Herviou L, Cavalli G, Cartron G, Klein B, Moreaux J. EZH2 in normal hematopoiesis and hematological malignancies. Oncotarget. 2016;7(3):2284–96. doi:10.18632/oncotarget.6198.

    Article  PubMed  Google Scholar 

  59. 59.

    Xu B, Konze KD, Jin J, Wang GG. Targeting EZH2 and PRC2 dependence as novel anticancer therapy. Exp Hematol. 2015;43(8):698–712. doi:10.1016/j.exphem.2015.05.001.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128–34. doi:10.1038/nm.4036.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Bradley WD, Arora S, Busby J, Balasubramanian S, Gehling VS, Nasveschuk CG, et al. EZH2 inhibitor efficacy in non-Hodgkin’s lymphoma does not require suppression of H3K27 monomethylation. Chem Biol. 2014;21(11):1463–75. doi:10.1016/j.chembiol.2014.09.017.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Volkel P, Dupret B, Le Bourhis X, Angrand PO. Diverse involvement of EZH2 in cancer epigenetics. Am J Transl Res. 2015;7(2):175–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492(7427):108. doi:10.1038/nature11606.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8(11):890–6. doi:10.1038/nchembio.1084.

    CAS  PubMed  Google Scholar 

  65. 65.

    Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13(4):842–54. doi:10.1158/1535-7163.MCT-13-0773.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013;110(19):7922–7. doi:10.1073/pnas.1303800110.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, et al. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J Med Chem. 2016;59(21):9928–41. doi:10.1021/acs.jmedchem.6b01315.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Miranda TB, Cortez CC, Yoo CB, Liang GN, Abe M, Kelly TK, et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther. 2009;8(6):1579–88. doi:10.1158/1535-7163.Mct-09-0013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD, et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol. 2013;9(10):643–50. doi:10.1038/nchembio.1331.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Fuhrmann J, Clancy KW, Thompson PR. Chemical biology of protein arginine modifications in epigenetic regulation. Chem Rev. 2015;115(11):5413–61. doi:10.1021/acs.chemrev.5b00003.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Tarighat SS, Santhanam R, Frankhouser D, Radomska HS, Lai H, Anghelina M, et al. The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia. 2016;30(4):789–99. doi:10.1038/leu.2015.308.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, et al. PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov. 2015;5(3):288–303. doi:10.1158/2159-8290.Cd-14-0625.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Gu ZP, Gao S, Zhang FH, Wang ZQ, Ma WC, Davis RE, et al. Protein arginine methyltransferase 5 is essential for growth of lung cancer cells. Biochem J. 2012;446:235–41. doi:10.1042/Bj20120768.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Zhang B, Dong S, Zhu R, Hu C, Hou J, Li Y, et al. Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3. Oncotarget. 2015;6(26):22799–811. doi:10.18632/oncotarget.4332.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Morettin A, Baldwin RM, Cote J. Arginine methyltransferases as novel therapeutic targets for breast cancer. Mutagenesis. 2015;30(2):177–89. doi:10.1093/mutage/geu039.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Koh CM, Bezzi M, Low DH, Ang WX, Teo SX, Gay FP, et al. Myc regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature. 2015;523(7558):96–100. doi:10.1038/nature14351.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11(6):432–7. doi:10.1038/nchembio.1810.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Song Y, Wu F, Wu J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J Hematol Oncol. 2016;9:49. doi:10.1186/s13045-016-0279-9.

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Schulte JH, Lim SY, Schramm A, Friedrichs N, Koster J, Versteeg R, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 2009;69(5):2065–71. doi:10.1158/0008-5472.Can-08-1735.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Zheng YC, Yu B, Jiang GZ, Feng XJ, He PX, Chu XY, et al. Irreversible LSD1 inhibitors: application of tranylcypromine and its derivatives in cancer treatment. Curr Top Med Chem. 2016;16(19):2179–88. doi:10.2174/1568026616666160216154042.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE, Van Aller GS, et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell. 2015;28(1):57–69. doi:10.1016/j.ccell.2015.06.002.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Lee SH, Liu XM, Diamond M, Dostalik V, Favata M, He C et al. The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of human small cell lung cancer. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res 2016;76:4704. doi:10.1158/1538-7445.Am2016-4704.

  83. 83.

    Lee SH, Stubbs M, Liu XM, Diamond M, Dostalik V, Ye M et al. Discovery of INCB059872, a novel FAD-directed LSDI inhibitor that is effective in preclinical models of human and murine AML. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res 2016;76:4712. doi:10.1158/1538-7445.Am2016-4712.

  84. 84.

    Ye M, Liu M, Lu J, Lo YN, Favata M, Yang GJ et al. The LSD1 inhibitor INCB059872 is synergistic with ATRA in models of non-APL acute myelogenous leukemia. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA April 16-20, 2016. Cancer Res 2016;76:4696. doi:10.1158/1538-7445.Am2016-4696.

  85. 85.

    Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2014;28(11):2155–64. doi:10.1038/leu.2014.119.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102(13):932–41. doi:10.1093/jnci/djq187.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016;21(117):373–80.

    PubMed  Google Scholar 

  88. 88.

    Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017;7(5):478–93. doi:10.1158/2159-8290.CD-16-1034.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (grant 2016YFA0502304) and the National Natural Science Foundation of China (grants 81230076).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Honglin Li.

Ethics declarations

Conflict of Interest

The authors indicate no conflict of interest with the subject matter of this review.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Epigenetics

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, Z., Li, H. Novel Drugs Targeting the Epigenome. Curr Pharmacol Rep 3, 268–285 (2017). https://doi.org/10.1007/s40495-017-0100-7

Download citation

Keywords

  • Epigenetic
  • Clinical trials
  • Inhibitors
  • Cancer
  • Cardiovascular