title: Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma.
abstract: Mutations within the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. Although both compounds are similar with respect to their mechanism of action and selectivity, EPZ-6438 possesses superior potency and drug-like properties, including good oral bioavailability in animals. Here, we characterize the activity of EPZ-6438 in preclinical models of NHL. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent manner in both EZH2 wild-type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) leads to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of EZH2-mutant NHL xenograft-bearing mice with EPZ-6438 causes dose-dependent tumor growth inhibition, including complete and sustained tumor regressions with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 days after stopping compound treatment in two EZH2-mutant xenograft models. These data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers.
authors.affiliation: Authors' Affiliations: Epizyme Inc., Cambridge; Eisai Inc., Andover, Massachusetts; and Eisai Co. Ltd., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawano
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Minoshima
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.forename: Kuan-Chun
authors.initials: KC
authors.lastname: Huang
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Mai
authors.initials: M
authors.lastname: Uesugi
authors.forename: Galina
authors.initials: G
authors.lastname: Kuznetsov
authors.forename: Namita
authors.initials: N
authors.lastname: Kumar
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.forename: Christine R
authors.initials: CR
authors.lastname: Klaus
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Allain
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Margaret
authors.initials: M
authors.lastname: Porter-Scott
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.forename: Akira
authors.initials: A
authors.lastname: Yokoi
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds; D020134:Catalytic Domain / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009025:Morpholines; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; D009025:Morpholines; D011728:Pyridones; D063151:Polycomb Repressive Complex 2; C000593333:tazemetostat