A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells

  • Nat Chem Biol. 2012 Nov;8(11):890-6. doi: 10.1038/nchembio.1084.
Sarah K Knutson  1 ,  Tim J Wigle ,  Natalie M Warholic ,  Christopher J Sneeringer ,  Christina J Allain ,  Christine R Klaus ,  Joelle D Sacks ,  Alejandra Raimondi ,  Christina R Majer ,  Jeffrey Song ,  Margaret Porter Scott ,  Lei Jin ,  Jesse J Smith ,  Edward J Olhava ,  Richard Chesworth ,  Mikel P Moyer ,  Victoria M Richon ,  Robert A Copeland ,  Heike Keilhack ,  Roy M Pollock ,  Kevin W Kuntz
Affiliations
  • 1. Epizyme, Inc., Cambridge, MA, USA.
PMID: 23023262 DOI: 10.1038/nchembio.1084
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.

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