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

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      Publication Details (including relevant citation   information):

        Nature Chemical Biology 2012 Nov; Vol 8(11): 890-896.

      Authors: Knutson SK, Wigle TJ,   Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD,   Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava   EJ, Chesworth R, Moyer MP, Richon VM, Copeland RA, Keilhack H,   Pollock RM, Kuntz KW



        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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