American Chemical Society
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Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity

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posted on 2023-06-08, 17:14 authored by Jiantao Hu, Biao Hu, Fuming Xu, Mi Wang, Chong Qin, Donna McEachern, Jeanne Stuckey, Shaomeng Wang
Starting from a nonselective bromodomain and extraterminal (BET) inhibitor and a cereblon ligand, we have used precise conformational control for the development of two potent and highly selective BRD4 degraders, BD-7148 and BD-9136. These compounds induce rapid degradation of BRD4 protein in cells at concentrations as low as 1 nM and demonstrate ≥1000-fold degradation selectivity over BRD2 or BRD3 protein. Proteomic analysis of >5700 proteins confirmed their highly selective BRD4 degradation. A single dose of BD-9136 selectively and effectively depletes BRD4 protein in tumor tissues for >48 h. BD-9136 effectively inhibits tumor growth without adverse effects on mice and is more efficacious than the corresponding pan BET inhibitor. This study suggests selective degradation of BRD4 as a strategy for the treatment of human cancers and demonstrates a strategy for the design of highly selective PROTAC degraders.