Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines.

Targeted degradation of BET family proteins BRD2/3/4 or only BRD4 with PROTAC molecules has been a promising strategy for the treatment of human cancer. Meanwhile, selective degradation of cellular BRD3 and BRD4-L remains a challenging task. We report herein a novel PROTAC molecule 24 that promoted selective degradation of cellular BRD3 and BRD4-L, but not BRD2 or BRD4-S, in a panel of six cancer cell lines. The observed target selectivity was partially attributed to differences in protein degradation kinetics and in types of cell lines. In a MM.1S mouse xenograft model, an optimized lead compound 28 promoted selective degradation of BRD3 and BRD4-L in vivo and exhibited robust antitumor activity. In summary, we have demonstrated that selective degradation of BRD3 and BRD4-L over BRD2 and BRD4-S is a feasible and robust approach in multiple cancer cell lines and an animal model, which could be helpful for further investigations on BRD3 and BRD4-L that ultimately benefitting cancer research and therapeutics.