Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.
Authors: Michael L Curtin, Marina A Pliushchev, Huan-Qiu Li, Maricel Torrent, Justin D Dietrich, Clarissa G Jakob, Haizhong Zhu, Hongyu Zhao, Ying Wang, Zhiqin Ji, Richard F Clark, Kathy A Sarris, Sujatha Selvaraju, Bailin Shaw, Mikkel A Algire, Yupeng He, Paul L Richardson, Ramzi F Sweis, Chaohong Sun, Gary G Chiang, Michael R Michaelides ,