Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation

  • Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5. doi: 10.1073/pnas.1210371110.
Wei Qi  1 ,  HoMan Chan ,  Lin Teng ,  Ling Li ,  Shannon Chuai ,  Ruipeng Zhang ,  Jue Zeng ,  Min Li ,  Hong Fan ,  Ying Lin ,  Justin Gu ,  Ophelia Ardayfio ,  Ji-Hu Zhang ,  Xiaoxia Yan ,  Jialuo Fang ,  Yuan Mi ,  Man Zhang ,  Tao Zhou ,  Grace Feng ,  Zijun Chen ,  Guobin Li ,  Teddy Yang ,  Kehao Zhao ,  Xianghui Liu ,  Zhengtian Yu ,  Chris X Lu ,  Peter Atadja ,  En Li
Affiliations
  • 1. China Novartis Institutes for BioMedical Research, Shanghai 201203, China.
PMID: 23236167 DOI: 10.1073/pnas.1210371110
Abstract

EZH2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of EZH2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of EZH2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of EZH2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of EZH2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and Apoptosis. These results provide strong validation of EZH2 as a potential therapeutic target for the treatment of Cancer.

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