title: A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.
abstract: EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 (K(i) of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered.
authors.affiliation: Epizyme, Inc., Cambridge, MA, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sneeringer
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Allain
authors.forename: Christine R
authors.initials: CR
authors.lastname: Klaus
authors.forename: Joelle D
authors.initials: JD
authors.lastname: Sacks
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.forename: Christina R
authors.initials: CR
authors.lastname: Majer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Song
authors.forename: Margaret Porter
authors.initials: MP
authors.lastname: Scott
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Olhava
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D015394:Molecular Structure; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C578195:EPZ005687; D004791:Enzyme Inhibitors; D006657:Histones; D007191:Indazoles; D011728:Pyridones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine