2089148-72-9Relevant articles and documents
SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding
Curtin, Michael L.,Pliushchev, Marina A.,Li, Huan-Qiu,Torrent, Maricel,Dietrich, Justin D.,Jakob, Clarissa G.,Zhu, Haizhong,Zhao, Hongyu,Wang, Ying,Ji, Zhiqin,Clark, Richard F.,Sarris, Kathy A.,Selvaraju, Sujatha,Shaw, Bailin,Algire, Mikkel A.,He, Yupeng,Richardson, Paul L.,Sweis, Ramzi F.,Sun, Chaohong,Chiang, Gary G.,Michaelides, Michael R.
, p. 1576 - 1583 (2017)
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.
