| Literature DB >> 28135235 |
Wei Qi1, Kehao Zhao1, Justin Gu1, Ying Huang1, Youzhen Wang1, Hailong Zhang1, Man Zhang1, Jeff Zhang1, Zhengtian Yu1, Ling Li1, Lin Teng1, Shannon Chuai1, Chao Zhang1, Mengxi Zhao1, HoMan Chan1, Zijun Chen1, Douglas Fang1, Qi Fei1, Leying Feng1, Lijian Feng1, Yuan Gao1, Hui Ge1, Xinjian Ge1, Guobin Li1, Andreas Lingel2, Ying Lin1, Yueqin Liu1, Fangjun Luo1, Minlong Shi1, Long Wang1, Zhaofu Wang1, Yanyan Yu1, Jue Zeng1, Chenhui Zeng1, Lijun Zhang1, Qiong Zhang1, Shaolian Zhou1, Counde Oyang1, Peter Atadja1, En Li1.
Abstract
Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.Entities:
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Year: 2017 PMID： 28135235 DOI： 10.1038/nchembio.2304
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040