posted on 2023-06-08, 17:14authored byJiantao 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.