Document Detail

A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.
MedLine Citation:
PMID:  23023262     Owner:  NLM     Status:  Publisher    
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.
Sarah K Knutson; 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
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-30
Journal Detail:
Title:  Nature chemical biology     Volume:  -     ISSN:  1552-4469     ISO Abbreviation:  Nat. Chem. Biol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101231976     Medline TA:  Nat Chem Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1] Epizyme, Inc., Cambridge, Massachusetts, USA. [2].
Data Bank Information
Bank Name/Acc. No.:
PubChem-Substance/144100026;  144100025;  144100027;  144100028
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