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Current Pharmacology Reports

, Volume 3, Issue 5, pp 268–285 | Cite as

Novel Drugs Targeting the Epigenome

  • Zhuo Chen
  • Honglin LiEmail author
Epigenetics ( ATY Lau, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Epigenetics

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.

Keywords

Epigenetic Clinical trials Inhibitors Cancer Cardiovascular 

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

Notes

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).

Compliance with Ethical Standards

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.

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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dawson MA. The cancer epigenome: concepts, challenges, and therapeutic opportunities. Science. 2017;355(6330):1147–52. doi: 10.1126/science.aam7304.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Medina-Franco J. Epi-informatics: discovery and development of small molecule epigenetic drugs and probes. Oxford: Academic Press; 2016. p. 440.Google Scholar
  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.PubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle Scholar
  12. 12.
    Garnock-Jones KP. Panobinostat: first global approval. Drugs. 2015;75(6):695–704. doi: 10.1007/s40265-015-0388-8.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128–34. doi: 10.1038/nm.4036.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.PubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of PharmacyEast China University of Science and TechnologyShanghaiChina

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