Discovery of highly potent and efficacious Bromodomain and Extra-terminal (BET) degraders with activity against acute myeloid leukemia and triple-negative breast cancer.

Bromodomain and extra-terminal (BET) family proteins are important epigenetic readers and play key roles in cancers, inflammatory diseases, and immune disorders. Current BET inhibitors, which function via an occupancy-driven mechanism, are often hampered by drug resistance and limited efficacy. In this study, a series of novel acetylpyrrole-based BET degraders were designed, synthesized, and evaluated, demonstrating notable antitumor effects in both wild-type and drug-resistant models of acute myeloid leukemia (AML) and triple-negative breast cancer (TNBC). Through structural optimization, 36 (F364) was identified as a potent BRD4 degrader, exhibiting a Dmax of 93.96% and a DC50 of 0.676 nM in the HiBiT assay using HEK293-BRD4-HiBiT-KI cells, slightly superior to the positive control ARV-825. This compound showed strong antiproliferative activity in MV4-11 cells (IC50 = 4.99 nM) and displayed marked efficacy against SHP099-resistant MV4-11 cells (IC50 = 1.62 nM), indicating its potential to overcome resistance to SHP2 inhibitors. Moreover, compound F364 exhibited an IC50 value of 127.87 nM against MDA-MB-231 cells, demonstrating potent antitumor activity toward solid tumor cells. Mechanistic investigations revealed that the degradation process involves the cereblon (CRBN)-mediated proteasomal pathway. In xenograft mouse models using MV4-11 and MDA-MB-231 cells, F364 demonstrated significant antitumor efficacy without observable toxicity. In summary, F364 has been identified as a novel and potent BRD4 degrader, showing promising therapeutic potential for the treatment of acute myeloid leukemia and triple-negative breast cancer.