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

• Published in: Nature chemical biology Vol. 8; no. 11; pp. 890 - 896
• Main Authors: 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, Kuntz, Kevin W
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2012; Nature Publishing Group
• Subjects: 631/208/176; 631/92/436/2388; 631/92/96; 692/699/67/1990/291/1621; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cancer therapies; Catalysts; Cell Biology; Cell Cycle - drug effects; Cell Death - drug effects; Cell Proliferation - drug effects; Chemistry; Chemistry/Food Science; Dose-Response Relationship, Drug; Enhancer of Zeste Homolog 2 Protein; Enzymatic activity; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Histones - chemistry; Histones - metabolism; Humans; Indazoles - chemistry; Indazoles - pharmacology; Inhibitors; Lymphoma; Lymphoma - drug therapy; Lymphoma - enzymology; Lymphoma - genetics; Lymphoma - pathology; Lysine - metabolism; Methylation; Methylation - drug effects; Molecular Structure; Mutagenesis; Mutation; Point Mutation; Polycomb Repressive Complex 2 - antagonists & inhibitors; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Pyridones - chemistry; Pyridones - pharmacology; Structure-Activity Relationship; Subpopulations
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1084

EZH2 is a protein methyltransferase component of the polycomb repressive complex 2 (PRC2) that installs the H3K27me3 chromatin mark. EPZ005687 inhibits EZH2 function and H3K27 trimethylation in cells and selectively kills lymphoma cells that require EZH2 for proliferation. 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.