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

Qi, Vicky, Chan, Ho Man, Atadja, Peter, Li, Ling, Chuai, Shannon, Lin, Ying, Gu, Justin, Zhang, Ji, Mi, Yuan, Zhang, Maya, Zhao, Kehao, Li, En, Teng, Lin, Zeng, Jue, Li, Min, Fan, Hong, Lin, Ying, Yan, Xiaoxia, Fang, Jialuo, Zhou, Tao, Feng, Grace, Yang, Teddy, Liu, Xianghui, Zhang, Regene, Li, Coben and Chen, Jason (2012) Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proceedings of National Academy of Sciences of the United States of America, 109 (52). pp. 21360-21365. ISSN 1091-6490


Ezh2 protein is the enzymatic component of the Polycomb Repressive Complex (PRC)-2, which represses its target genes by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 have been identified in diffused large B cell lymphomas (DLBCLs) and follicular lymphomas (FLs). To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we have developed a potent and selective small molecule inhibitor, JAD593, which inhibits the enzymatic activity of Ezh2 through direct binding and competing with the methyl group donor S-Adenosyl methionine (SAM). JAD593-treated cells exhibit genome-wide loss of H3K27 methylation. Furthermore, inhibition of Ezh2 by JAD593 in DLBCL 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 with the Ezh2 mutation.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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