2. Academic Validation
  3. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

  • Nat Chem Biol. 2017 Apr;13(4):381-388. doi: 10.1038/nchembio.2304.
Wei Qi 1,  Kehao Zhao 1,  Justin Gu 1,  Ying Huang 1,  Youzhen Wang 1,  Hailong Zhang 1,  Man Zhang 1,  Jeff Zhang 1,  Zhengtian Yu 1,  Ling Li 1,  Lin Teng 1,  Shannon Chuai 1,  Chao Zhang 1,  Mengxi Zhao 1,  HoMan Chan 1,  Zijun Chen 1,  Douglas Fang 1,  Qi Fei 1,  Leying Feng 1,  Lijian Feng 1,  Yuan Gao 1,  Hui Ge 1,  Xinjian Ge 1,  Guobin Li 1,  Andreas Lingel 2,  Ying Lin 1,  Yueqin Liu 1,  Fangjun Luo 1,  Minlong Shi 1,  Long Wang 1,  Zhaofu Wang 1,  Yanyan Yu 1,  Jue Zeng 1,  Chenhui Zeng 1,  Lijun Zhang 1,  Qiong Zhang 1,  Shaolian Zhou 1,  Counde Oyang 1,  Peter Atadja 1,  En Li 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Shanghai, China.
  • 2 Novartis Institutes for BioMedical Research, Emeryville, California, USA.
PMID: 28135235 DOI: 10.1038/nchembio.2304
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.

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