| Literature DB >> 28135237 |
Yupeng He1, Sujatha Selvaraju1, Michael L Curtin1, Clarissa G Jakob1, Haizhong Zhu1, Kenneth M Comess1, Bailin Shaw1, Juliana The2, Evelyne Lima-Fernandes2,3, Magdalena M Szewczyk2, Dong Cheng1, Kelly L Klinge1, Huan-Qiu Li1, Marina Pliushchev1, Mikkel A Algire1, David Maag1, Jun Guo1, Justin Dietrich1, Sanjay C Panchal1, Andrew M Petros1, Ramzi F Sweis1, Maricel Torrent1, Lance J Bigelow1, Guillermo Senisterra2, Fengling Li2, Steven Kennedy2, Qin Wu2,3, Donald J Osterling1, David J Lindley1, Wenqing Gao1, Scott Galasinski1, Dalia Barsyte-Lovejoy2, Masoud Vedadi2,4, Fritz G Buchanan1, Cheryl H Arrowsmith2,3, Gary G Chiang1,5, Chaohong Sun1, William N Pappano1.
Abstract
Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.Entities:
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Year: 2017 PMID： 28135237 DOI： 10.1038/nchembio.2306
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040