The Bromo- and Extra-Terminal (BET) proteins, including BRD2, BRD3, and BRD4 proteins are epigenetic reader proteins and attractive new therapeutic targets for human cancers and other diseases. Several small-molecule BET inhibitors are currently in clinical development for cancer treatment. Recently, Proteolysis Targeted Chimeras (PROTAC)-based small-molecule degraders of BET (BET degraders) have been developed and demonstrate much improved potency in vitro and in vivo in different tumor models over small-molecule BET inhibitors. We present herein our design, synthesis, and evaluation of a new class of BET degraders based upon our Carboline-containing BET inhibitors. Our most potent BET degrader ZBC260 can effectively induce rapid degradation of BET proteins in leukemia and solid tumor cells at pico-molar to sub-nanomolar concentrations. ZBC260 achieve IC50 values of pico-molar to sub-nanomolar in inhibition of cell growth against human leukemia and solid tumor cell lines. Significantly, ZBC260 can induce rapid and complete tumor regression in animal models of human cancer at well tolerated dose-schedules in mice. ZBC260 represents the most potent BET degrader reported to date and a promising lead compound for extensive testing as a potential new therapy for cancer and other human diseases.

Discovery of a new class of highly potent small-molecule degraders of BET bromodomain proteins

253rd National Meeting (2017)

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