EZH2 inhibitors: a patent review (2014-2016)

References

• Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978 Dec 7;276(5688):565–570.
   PubMed Web of Science ®Google Scholar
• Whitcomb SJ, Basu A, Allis CD, et al. Polycomb Group proteins: an evolutionary perspective. Trends Genet. 2007 Oct;23(10):494–502.
   PubMed Web of Science ®Google Scholar
• Schuettengruber B, Cavalli G. Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development. 2009 Nov;136(21):3531–3542.
   PubMed Web of Science ®Google Scholar
• Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009 Oct;10(10):697–708.
   PubMed Web of Science ®Google Scholar
• Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002 Nov 1;298(5595):1039–1043.
   PubMed Web of Science ®Google Scholar
• Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011 Jan 20;469(7330):343–349.
   PubMed Web of Science ®Google Scholar
• Margueron R, Li G, Sarma K, et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell. 2008 Nov 21;32(4):503–518.
   PubMed Web of Science ®Google Scholar
• Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004 Jul 2;15(1):57–67.
   PubMed Web of Science ®Google Scholar
• Ketel CS, Andersen EF, Vargas ML, et al. Subunit contributions to histone methyltransferase activities of fly and worm polycomb group complexes. Mol Cell Biol. 2005 Aug;25(16):6857–6868.
   PubMed Web of Science ®Google Scholar
• Pasini D, Bracken AP, Jensen MR, et al. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. Embo J. 2004 Oct 13;23(20):4061–4071.
   PubMed Web of Science ®Google Scholar
• Agger K, Cloos PA, Christensen J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007 Oct 11;449(7163):731–734.
   PubMed Web of Science ®Google Scholar
• Hong S, Cho YW, Yu LR, et al. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439–18444.
   PubMed Web of Science ®Google Scholar
• Lee MG, Villa R, Trojer P, et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science. 2007 Oct 19;318(5849):447–450.
   PubMed Web of Science ®Google Scholar
• Lan F, Bayliss PE, Rinn JL, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007 Oct 11;449(7163):689–694.
   PubMed Web of Science ®Google Scholar
• De Santa F, Totaro MG, Prosperini E, et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007 Sep 21;130(6):1083–1094.
   PubMed Web of Science ®Google Scholar
• Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016 Feb;22(2):128–134.
   PubMed Web of Science ®Google Scholar
• Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004 Apr;14(2):155–164.
   PubMed Web of Science ®Google Scholar
• Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006 Apr 21;125(2):301–313.
   PubMed Web of Science ®Google Scholar
• Bracken AP, Pasini D, Capra M, et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. Embo J. 2003 Oct 15;22(20):5323–5335.
   PubMed Web of Science ®Google Scholar
• Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, et al. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev. 2005 Jun 15;19(12):1438–1443.
   PubMed Web of Science ®Google Scholar
• Cao Q, Yu J, Dhanasekaran SM, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008 Dec 11;27(58):7274–7284.
   PubMed Web of Science ®Google Scholar
• Chang CJ, Yang JY, Xia W, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell. 2011 Jan 18;19(1):86–100.
   PubMed Web of Science ®Google Scholar
• Du J, Li L, Ou Z, et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res Treat. 2012 Jan;131(1):65–73.
   PubMed Web of Science ®Google Scholar
• Koh CM, Iwata T, Zheng Q, et al. Myc enforces overexpression of EZH2 in early prostatic neoplasia via transcriptional and post-transcriptional mechanisms. Oncotarget. 2011 Sep;2(9):669–683.
   PubMed Web of Science ®Google Scholar
• Muller H, Bracken AP, Vernell R, et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 2001 Feb 1;15(3):267–285.
   PubMed Web of Science ®Google Scholar
• Neri F, Zippo A, Krepelova A, et al. Myc regulates the transcription of the PRC2 gene to control the expression of developmental genes in embryonic stem cells. Mol Cell Biol. 2012 Feb;32(4):840–851.
   PubMed Web of Science ®Google Scholar
• Benetatos L, Voulgaris E, Vartholomatos G, et al. Non-coding RNAs and EZH2 interactions in cancer: long and short tales from the transcriptome. Int J Cancer. 2013 Jul 15;133(2):267–274.
   PubMed Web of Science ®Google Scholar
• Caretti G, Palacios D, Sartorelli V, et al. Phosphoryl-EZH-ion. Cell Stem Cell. 2011 Mar 4;8(3):262–265.
   PubMed Web of Science ®Google Scholar
• Cakouros D, Isenmann S, Cooper L, et al. Twist-1 induces Ezh2 recruitment regulating histone methylation along the Ink4A/Arf locus in mesenchymal stem cells. Mol Cell Biol. 2012 Apr;32(8):1433–1441.
   PubMed Web of Science ®Google Scholar
• Corvetta D, Chayka O, Gherardi S, et al. Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: functional and therapeutic implications. J Biol Chem. 2013 Mar 22;288(12):8332–8341.
   PubMed Web of Science ®Google Scholar
• Chang CJ, Hung MC. The role of EZH2 in tumour progression. Br J Cancer. 2012 Jan 17;106(2):243–247.
   PubMed Web of Science ®Google Scholar
• Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011 May 1;17(9):2613–2618.
   PubMed Web of Science ®Google Scholar
• Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002 Oct 10;419(6907):624–629.
   PubMed Web of Science ®Google Scholar
• Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606–11611.
   PubMed Web of Science ®Google Scholar
• Bachmann IM, Halvorsen OJ, Collett K, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006 Jan 10;24(2):268–273.
   PubMed Web of Science ®Google Scholar
• Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010 Sep 3;7(3):299–313.
   PubMed Web of Science ®Google Scholar
• Herrera-Merchan A, Arranz L, Ligos JM, et al. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun. 2012 Jan 10;3:623.
   PubMed Web of Science ®Google Scholar
• Luo H, Jiang Y, Ma S, et al. EZH2 promotes invasion and metastasis of laryngeal squamous cells carcinoma via epithelial-mesenchymal transition through H3K27me3. Biochem Biophys Res Commun. 2016 Oct 14;479(2):253–259.
   PubMed Web of Science ®Google Scholar
• Cardenas H, Zhao J, Vieth E, et al. EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells. Oncotarget. 2016 Dec 20;7(51):84453–84467.
   PubMed Web of Science ®Google Scholar
• Honma K, Udono H, Kohno T, et al. Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. Proc Natl Acad Sci U S A. 2005 Nov 01;102(44):16001–16006.
   PubMed Web of Science ®Google Scholar
• Yoshida H, Nadanaka S, Sato R, et al. XBP1 is critical to protect cells from endoplasmic reticulum stress: evidence from Site-2 protease-deficient Chinese hamster ovary cells. Cell Struct Funct. 2006;31(2):117–125.
   PubMed Web of Science ®Google Scholar
• Turner CA Jr., Mack DH, Davis MM. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell. 1994 Apr 22;77(2):297–306.
   PubMed Web of Science ®Google Scholar
• Sciammas R, Davis MM. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. J Immunol. 2004 May 01;172(9):5427–5440.
   PubMed Web of Science ®Google Scholar
• Alzrigat M, Parraga AA, Agarwal P, et al. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. Oncotarget. 2017 Feb 7;8(6):10213–10224.
   PubMed Web of Science ®Google Scholar
• Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010 Feb;42(2):181–185.
   PubMed Web of Science ®Google Scholar
• McCabe MT, Graves AP, Ganji G, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2989–2994.
   PubMed Web of Science ®Google Scholar
• Sneeringer CJ, Scott MP, Kuntz KW, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20980–20985.
   PubMed Web of Science ®Google Scholar
• Boyer LA, Plath K, Zeitlinger J, et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006 May 18;441(7091):349–353.
   PubMed Web of Science ®Google Scholar
• Ezhkova E, Pasolli HA, Parker JS, et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009 Mar 20;136(6):1122–1135.
   PubMed Web of Science ®Google Scholar
• Piunti A, Pasini D. Epigenetic factors in cancer development: polycomb group proteins. Future Oncol. 2011 Jan;7(1):57–75.
   PubMed Web of Science ®Google Scholar
• Karantanos T, Chistofides A, Barhdan K, et al. Regulation of T cell differentiation and function by EZH2. Front Immunol. 2016;7:172.
   PubMed Web of Science ®Google Scholar
• Caretti G, Di Padova M, Micales B, et al. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 2004 Nov 1;18(21):2627–2638.
   PubMed Web of Science ®Google Scholar
• Sher F, Rossler R, Brouwer N, et al. Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2. Stem Cells. 2008 Nov;26(11):2875–2883.
   PubMed Web of Science ®Google Scholar
• Hwang WW, Salinas RD, Siu JJ, et al. Distinct and separable roles for EZH2 in neurogenic astroglia. Elife. 2014 May 27;3:e02439.
   PubMed Web of Science ®Google Scholar
• Pereira JD, Sansom SN, Smith J, et al. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15957–15962.
   PubMed Web of Science ®Google Scholar
• Acharyya S, Sharma SM, Cheng AS, et al. TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: implications in duchenne muscular dystrophy. PLoS One. 2010 Aug 30;5(8):e12479.
   PubMed Web of Science ®Google Scholar
• Palacios D, Mozzetta C, Consalvi S, et al. TNF/p38alpha/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell. 2010 Oct 8;7(4):455–469.
   PubMed Web of Science ®Google Scholar
• Chen H, Gu X, Su IH, et al. Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 2009 Apr 15;23(8):975–985.
   PubMed Web of Science ®Google Scholar
• Zhou JX, Dhawan S, Fu H, et al. Combined modulation of polycomb and trithorax genes rejuvenates beta cell replication. J Clin Invest. 2013 Nov;123(11):4849–4858.
   PubMed Web of Science ®Google Scholar
• Wei Y, Chen YH, Li LY, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011 Jan;13(1):87–94.
   PubMed Web of Science ®Google Scholar
• Chen YH, Yeh FL, Yeh SP, et al. Myocyte enhancer factor-2 interacting transcriptional repressor (MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells by inactivating peroxisome proliferator-activated receptor gamma-2. J Biol Chem. 2011 Mar 25;286(12):10671–10680.
   PubMed Web of Science ®Google Scholar
• Wang L, Jin Q, Lee JE, et al. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7317–7322.
   PubMed Web of Science ®Google Scholar
• Tanaka M, Roberts JM, Qi J, et al. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010-2014). Pharm Pat Anal. 2015;4(4):261–284.
   PubMed Web of Science ®Google Scholar
• Glazer RI, Knode MC, Tseng CK, et al. 3-Deazaneplanocin A: a new inhibitor of S-adenosylhomocysteine synthesis and its effects in human colon carcinoma cells. Biochem Pharmacol. 1986 Dec 15;35(24):4523–4527.
   PubMed Web of Science ®Google Scholar
• Miranda TB, Cortez CC, Yoo CB, et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther. 2009 Jun;8(6):1579–1588.
   PubMed Web of Science ®Google Scholar
• Tan J, Yang X, Zhuang L, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007 May 1;21(9):1050–1063.
   PubMed Web of Science ®Google Scholar
• Sun F, Lee L, Zhang Z, et al. Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus. Eur J Pharm Sci. 2015 Sep 18;77:290–302.
   PubMed Web of Science ®Google Scholar
• Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012 Nov;8(11):890–896.
   PubMed Web of Science ®Google Scholar
• Morera L, Lubbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics. 2016;8:57.
   PubMed Web of Science ®Google Scholar
• Yap TA, Winter JN, Leonard JP, et al. A phase I study of GSK2816126, an enhancer of zeste homolog 2(EZH2) inhibitor, in patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), other non-hodgkin lymphomas (NHL), transformed follicular lymphoma (tFL), solid tumors and multiple myeloma (MM). Blood. 2016;128(22):4203.
   Web of Science ®Google Scholar
• Verma SK, Tian X, LaFrance LV, et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett. 2012 Dec 13;3(12):1091–1096.
   PubMed Web of Science ®Google Scholar
• Qi W, Chan H, Teng L, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360–21365.
   PubMed Web of Science ®Google Scholar
• Konze KD, Ma A, Li F, et al. An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324–1334.
   PubMed Web of Science ®Google Scholar
• Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922–7927.
   PubMed Web of Science ®Google Scholar
• Kuntz KW, Campbell JE, inventors; Epizyme, Inc., USA. assignee. Preparation of 1,4-pyridone compounds and useful in the treatment of cancer patent WO2014100646A1. 2014.
   Google Scholar
• Kuntz KW, Choi H-W, Mathieu S, et al., inventors; Epizyme, Inc., USA; Eisai R&D Management Co., Ltd. assignee. Preparation of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4’-(morpholinomethyl)-[1,1’-biphenyl]-3-carboxamide monohydrochloride polymorph as an EZH2 inhibitor for cancer treatment patent WO2015057859A1. 2015.
   Google Scholar
• Keilhack H, Truitt B, Suzuki Y, et al., inventors; Epizyme, Inc., USA; Eisai R&D Management Co., Ltd. assignee. Method for treating cancer using histone methyltransferase EZH2 inhibitors patent WO2016081523A1. 2016.
   Google Scholar
• Ribrag V, Soria J-C, Michot J-M, et al. Phase 1 study of tazemetostat (EPZ-6438), an inhibitor of enhancer of zeste-homolog 2 (EZH2): preliminary safety and activity in relapsed or refractory non-Hodgkin lymphoma (NHL) patients. Blood. 2015;126(23):473–473.
   Google Scholar
• Nasveschuk CG, Gagnon A, Garapaty-Rao S, et al. Discovery and optimization of tetramethylpiperidinyl benzamides as inhibitors of EZH2. ACS Med Chem Lett. 2014 Apr 10;5(4):378–383.
   PubMed Web of Science ®Google Scholar
• Gehling VS, Vaswani RG, Nasveschuk CG, et al. Discovery, design, and synthesis of indole-based EZH2 inhibitors. Bioorg Med Chem Lett. 2015 Sep 1;25(17):3644–3649.
   PubMed Web of Science ®Google Scholar
• Vaswani RG, Gehling VS, Dakin LA, 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 Nov 10;59(21):9928–9941.
   PubMed Web of Science ®Google Scholar
• Campbell JE, Kuntz KW, Knutson SK, et al. EPZ011989, A potent, orally-available EZH2 inhibitor with robust in vivo activity. ACS Med Chem Lett. 2015 May 14;6(5):491–495.
   PubMed Web of Science ®Google Scholar
• Kuntz KW, Campbell JE, Seki M, inventors; Epizyme, Inc., USA. assignee. Preparation of substituted benzene compounds as anticancer agents patent US20140107122A1. 2014.
   Google Scholar
• Campbell JE, Kuntz KW, inventors; Epizyme, Inc., USA. assignee. Preparation of substituted 6,5-fused bicyclic heteroaryl compounds as anticancer agents EZH2-mediated cancers patent WO2014144747A1. 2014.
   Google Scholar
• Campbell JE, inventor Epizyme, Inc., USA. assignee. Substituted 6,5-fused bicyclic heteroaryl compounds patent WO2015010078A2. 2015.
   Google Scholar
• Campbell JE, inventor Epizyme, Inc., USA. assignee. Preparation of substituted benzene compounds for treating cancer patent WO2015010049A1. 2015.
   Google Scholar
• Campbell JE, inventor Epizyme, Inc., USA. assignee. Substituted benzene and 6,5-fused bicyclic heteroaryl compounds patent WO2015200650A1. 2015.
   Google Scholar
• Miller WH, Romeril SP, Verma SK, et al., inventors; GlaxoSmithKline Intellectual Property No.2 Limited, UK. assignee. Preparation of pyridoazacyclotridecinoindole compounds as enhancer of zeste homolog 2 inhibitors for treating cancer patent WO2015132765A1. 2015.
   Google Scholar
• Burgess JL, Knight SD, inventors; GlaxoSmithKline Intellectual Property No.2 Limited, UK. assignee. Preparation of thiophenecarboxamide derivatives as enhancer of zeste homolog 2 inhibitors for the treatment of cancer patent WO2015004618A1. 2015.
   Google Scholar
• Knight SD, Newlander KA, Tian X, inventors; GlaxoSmithKline Intellectual Property No.2 Limited, UK. assignee. Preparation of N-oxopyridinylmethyl thiophenecarboxamides as enhancer of zeste homolog 2 inhibitors patent WO2016066697A1. 2016.
   Google Scholar
• Albrecht BK, Audia JE, Cook AS, et al., inventors; Constellation Pharmaceuticals, Inc., USA. assignee. Preparation of methyloxodihydropyridinylmethylcarbamoylmethylindole derivatives and analogs for use as histone methyl modifying enzyme modulators patent WO2014124418A1. 2014.
   Google Scholar
• Albrecht BK, Audia JE, Dakin LA, et al., inventors; Constellation Pharmaceuticals, Inc., USA. assignee. Preparation of indole derivatives as modulators of methyl modifying enzymes patent WO2015023915A1. 2015.
   Google Scholar
• Albrecht BK, Gehling VC, Harmange J-C, et al., inventors; Constellation Pharmaceuticals, Inc., USA. assignee. Preparation of substituted indolecarboxamides as modulators of methyl modifying enzymes patent WO2016130396A1. 2016.
   Google Scholar
• Kim KS, Zhang L, Purandare AV, et al., inventors; Bristol-Myers Squibb Company, USA. assignee. Preparation of substituted dihydroisoquinolines as inhibitors of histone-lysine N-methyltransferase patent WO2015077193A1. 2015.
   Google Scholar
• Seitz SP, Markwalder JA, Purandare AV, inventors; Bristol-Myers Squibb Company, USA. assignee. Preparation of N-((2-oxo-1,2-dihydropyridin-3-yl)methyl) amides as inhibitors of lysine methyl transferase patent WO2015077194A1. 2015.
   Google Scholar
• Kumpf RA, Kung -P-P, Sutton SC, et al., inventors; Pfizer Inc., USA. assignee. Preparation of aryl fused lactams as EZH2 modulators patent WO2015193768A1. 2015.
   Google Scholar
• Kung PP, Rui E, Bergqvist S, et al. Design and synthesis of pyridone-containing 3,4-dihydroisoquinoline-1(2h)-ones as a novel class of enhancer of zeste homolog 2 (EZH2) inhibitors. J Med Chem. 2016 Sep 22;59(18):8306–8325.
   PubMed Web of Science ®Google Scholar
• Collins MR, Kania RS, Kumpf RA, et al., inventors; Pfizer Inc., USA. assignee. Substituted dihydroisoquinolinone compounds as EZH2 inhibitors and their preparation patent US20150361067A1. 2015.
   Google Scholar
• Bradner JE, Qi J, Wong KK, inventors; Dana-Farber Cancer Institute, Inc., USA. assignee. EZH2 inhibitors and uses thereof patent WO2016073956A1. 2016.
   Google Scholar
• Zhang H, Qi J, Reyes JM, et al. Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discov. 2016 Sep;6(9):1006–1021.
   PubMed Web of Science ®Google Scholar
• Bradner JE, Blazar B, Flynn R, et al., inventors; Dana-Farber Cancer Institute, Inc., USA; Regents of the University of Minnesota. assignee. Use of compositions modulating chromatin structure for graft versus host disease patent WO2016073903A1. 2016.
   Google Scholar
• Fernandez-Montalvan A, Stresemann C, Christ C, et al., inventors; Bayer Pharma Aktiengesellschaft, Germany; The Broad Institute Inc.. assignee. Imidazopyridine as EZH2 inhibitors and their preparation patent WO2016102493A1. 2016.
   Google Scholar
• Guo D, Yu K-L, inventors; Eli Lilly and Company, USA. assignee. Preparation of N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl]-4-methylthiophene-3-carboxamide and its isomer as inhibitors of EXH2 patent WO2016089804A1. 2016.
   Google Scholar
• Brooun A, Gajiwala KS, Deng YL, et al. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat Commun. 2016 Apr 28;7:11384.
   PubMed Web of Science ®Google Scholar
• Yang X, Li F, Konze KD, et al. Structure-activity relationship studies for enhancer of zeste homologue 2 (EZH2) and enhancer of zeste homologue 1 (EZH1) inhibitors. J Med Chem. 2016 Aug 25;59(16):7617–7633.
   PubMed Web of Science ®Google Scholar
• Gibaja V, Shen F, Harari J, et al. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene. 2016 Feb 4;35(5):558–566.
   PubMed Web of Science ®Google Scholar
• Baude A, Lindroth AM, Plass C. PRC2 loss amplifies Ras signaling in cancer. Nat Genet. 2014 Nov;46(11):1154–1155.
   PubMed Web of Science ®Google Scholar
• De Raedt T, Walton Z, Yecies JL, et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell. 2011 Sep 13;20(3):400–413.
   PubMed Web of Science ®Google Scholar
• Benedetti R, Conte M, Iside C, et al. Epigenetic-based therapy: from single- to multi-target approaches. Int J Biochem Cell Biol. 2015;69:121–131.
   PubMed Web of Science ®Google Scholar
• De Lera AR, Ganesan A. Epigenetic polypharmacology: from combination therapy to multitargeted drugs. Clin Epigenetics. 2016;8:105.
   PubMed Web of Science ®Google Scholar
• Knutson SK, Warholic NM, Johnston LD, et al. Synergistic anti-tumor activity of EZH2 inhibitors and glucocorticoid receptor agonists in models of germinal center non-hodgkin lymphomas. PLoS One. 2014;9(12):e111840.
   PubMed Web of Science ®Google Scholar
• Kirk JS, Schaarschuch K, Dalimov Z, et al. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer. Oncotarget. 2015 Feb 20;6(5):3136–3146.
   PubMed Web of Science ®Google Scholar
• Kim W, Bird GH, Neff T, et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol. 2013 Oct;9(10):643–650.
   PubMed Web of Science ®Google Scholar
• Walensky LD, inventor Dana-Farber Cancer Institute, Inc., USA. assignee. Stabilized EZH2 peptides for treatment of cancer patent WO2014151369A2. 2014.
   Google Scholar
• Kong X, Chen L, Jiao L, et al. Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2. J Med Chem. 2014 Nov 26;57(22):9512–9521.
   PubMed Web of Science ®Google Scholar
• Chen H, Gao S, Li J, et al. Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer. Oncotarget. 2015 May 30;6(15):13049–13059.
   PubMed Web of Science ®Google Scholar
• Li L, Zhang H, Zhang M, et al. Discovery and molecular basis of a diverse set of polycomb repressive complex 2 inhibitors recognition by EED. PLoS One. 2017;12(1):e0169855.
   PubMed Web of Science ®Google Scholar
• Lingel A, Sendzik M, Huang Y, et al. Structure-guided design of EED binders allosterically inhibiting the epigenetic polycomb repressive complex 2 (PRC2) methyltransferase. J Med Chem. 2017 Jan 12;60(1):415–427.
   PubMed Web of Science ®Google Scholar
• Huang Y, Zhang J, Yu Z, et al. Discovery of first-in-class, potent and orally bioavailable EED inhibitor with robust anti-cancer efficacy. J Med Chem. 2017 Mar 23;60(6):2215–2226.
   PubMed Web of Science ®Google Scholar
• He Y, Selvaraju S, Curtin ML, et al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 2017 Apr;13(4):389–395.
   PubMed Web of Science ®Google Scholar
• Qi W, Zhao K, Gu J, et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol. 2017 Jan 30;13:381–388.
   PubMed Web of Science ®Google Scholar
• Xu B, On DM, Ma A, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood. 2015 Jan 8;125(2):346–357.
   PubMed Web of Science ®Google Scholar