Journal Article

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

Pliushchev, Marina, Shaw, Bailin, Barsyte-Lovejoy, Dalia, Comess, Kenneth M, Petros, Andrew M, Bigelow, Lance J, Osterling, Donald J, Vedadi, Masoud, Selvaraju, Sujatha, Lindley, David J, Gao, Wenqing, Senisterra, Guillermo, Algire, Mikkel A, Kennedy, Steven, Panchal, Sanjay C, Pappano, William N, He, Yupeng, Cheng, Dong, Arrowsmith, Cheryl H, Chiang, Gary G, Wu, Qin, The, Juliana, Sweis, Ramzi F, Li, Fengling, Szewczyk, Magdalena M, Klinge, Kelly L, Zhu, Haizhong, Lima-Fernandes, Evelyne, Li, Huan-Qiu, Sun, Chaohong, Dietrich, Justin, Maag, David, Jakob, Clarissa G, Galasinski, Scott, Buchanan, Fritz G, Guo, Jun, Curtin, Michael L, Torrent, Maricel

2017

Overview

A pyrrolidine-based small-molecule inhibitor competes with H3K27me3 for binding to EED leading to inactivation of PRC2 and global reduction in H3K27me3 levels. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/1647/2258/1266 / 631/337/100/2285 / 631/67/1059 / 631/92/613 / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / BASIC BIOLOGICAL SCIENCES / Binding sites / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Cell cycle / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Survival - drug effects / Chemistry / Chemistry/Food Science / Dose-Response Relationship, Drug / Drug Screening Assays, Antitumor / Enzymes / Epigenetics / Humans / Indans - chemistry / Indans - pharmacology / Lymphoma / Models, Molecular / Molecular Structure / Mutation / Polycomb Repressive Complex 2 - antagonists & inhibitors / Polycomb Repressive Complex 2 - chemistry / Polycomb Repressive Complex 2 - metabolism / Protein Binding - drug effects / Proteins / Structure-Activity Relationship / Sulfonamides - chemistry / Sulfonamides - pharmacology / Tumor Cells, Cultured