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Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

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posted on 18.07.2018, 00:00 by Chong Qin, Yang Hu, Bing Zhou, Ester Fernandez-Salas, Chao-Yie Yang, Liu Liu, Donna McEachern, Sally Przybranowski, Mi Wang, Jeanne Stuckey, Jennifer Meagher, Longchuan Bai, Zhuo Chen, Mei Lin, Jiuling Yang, Danya N. Ziazadeh, Fuming Xu, Jiantao Hu, Weiguo Xiang, Liyue Huang, Siwei Li, Bo Wen, Duxin Sun, Shaomeng Wang
Proteins of the bromodomain and extra-terminal (BET) family are epigenetics “readers” and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]­oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.