The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.
Keywords: BRD4 and BRD2; Cancers; PROTAC degraders; Selectivity.
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