The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex

被引：171

作者：

He, Yupeng ^{[1
]}

Selvaraju, Sujatha ^{[1
]}

Curtin, Michael L. ^{[1
]}

Jakob, Clarissa G. ^{[1
]}

Zhu, Haizhong ^{[1
]}

Comess, Kenneth M. ^{[1
]}

Shaw, Bailin ^{[1
]}

The, Juliana ^{[2
]}

Lima-Fernandes, Evelyne ^{[2
,3
,4
]}

Szewczyk, Magdalena M. ^{[2
]}

Cheng, Dong ^{[1
]}

Klinge, Kelly L. ^{[1
]}

Li, Huan-Qiu ^{[1
]}

Pliushchev, Marina ^{[1
]}

Algire, Mikkel A. ^{[1
]}

Maag, David ^{[1
]}

Guo, Jun ^{[1
]}

Dietrich, Justin ^{[1
]}

Panchal, Sanjay C. ^{[1
]}

Petros, Andrew M. ^{[1
]}

Sweis, Ramzi F. ^{[1
]}

Torrent, Maricel ^{[1
]}

Bigelow, Lance J. ^{[1
]}

Senisterra, Guillermo ^{[2
]}

Li, Fengling ^{[2
]}

Kennedy, Steven ^{[2
]}

Wu, Qin ^{[2
,3
,4
]}

Osterling, Donald J. ^{[1
]}

Lindley, David J. ^{[1
]}

Gao, Wenqing ^{[1
]}

Galasinski, Scott ^{[1
]}

Barsyte-Lovejoy, Dalia ^{[2
]}

Vedadi, Masoud ^{[2
,5
]}

Buchanan, Fritz G. ^{[1
]}

Arrowsmith, Cheryl H. ^{[2
,3
,4
]}

Chiang, Gary G. ^{[1
,6
]}

Sun, Chaohong ^{[1
]}

Pappano, William N. ^{[1
]}

机构：

[1] AbbVie Inc, N Chicago, IL 60064 USA

[2] Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada

[3] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON, Canada

[4] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[5] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada

[6] eFFECTOR Therapeut, San Diego, CA USA

来源：

NATURE CHEMICAL BIOLOGY | 2017年 / 13卷 / 04期

基金：

巴西圣保罗研究基金会; 加拿大健康研究院; 加拿大创新基金会; 英国惠康基金;

关键词：

POLYCOMB REPRESSIVE COMPLEX; B-CELL LYMPHOMA; THERMAL SHIFT ASSAYS; HISTONE H3; DRUG DISCOVERY; LYSINE; 27; METHYLTRANSFERASE ACTIVITY; SELECTIVE INHIBITOR; H3K27; METHYLATION; EZH2; INHIBITION;

D O I：

10.1038/nchembio.2306

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：389 / +

页数：10

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