학술논문
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.
Document Type
Article
Author
Knutson, Sarah K; Wigle, Tim J; Warholic, Natalie M; Sneeringer, Christopher J; Allain, Christina J; Klaus, Christine R; Sacks, Joelle D; Raimondi, Alejandra; Majer, Christina R; Song, Jeffrey; Scott, Margaret Porter; Jin, Lei; Smith, Jesse J; Olhava, Edward J; Chesworth, Richard; Moyer, Mikel P; Richon, Victoria M; Copeland, Robert A; Keilhack, Heike; Pollock, Roy M
Source
Subject
*LYMPHOMAS
*HISTONE methylation
*CANCER cells
*ENZYME inhibitors
*POINT mutation (Biology)
*APOPTOSIS
*METHYLTRANSFERASES
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Language
ISSN
1552-4450
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 (Ki 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. [ABSTRACT FROM AUTHOR]