Development of Prostate Cancer-Targeting BRD4 Intramolecular Bivalent Molecular Glue Degraders

Molecular glue degraders and PROTACs (proteolysis targeting chimeras) are promising therapeutic modalities by hijacking ubiquitin-proteasome pathway to degrade cellular proteins of interests (POIs). However, their clinical applications are often constrained by on-target, off-tissue toxicity. In this study, we present a prostate cancer-targeting delivery strategy for the development of highly potent and selective BRD4 degraders. The tissue-selective degraders are composed of recently reported highly potent BRD4 intramolecular bivalent molecular glue degraders and ligands of prostate-specific membrane antigen (PSMA). The selective degradation of BRD4 was validated both in vitro and in vivo. The mechanism of action was further confirmed through PSMA inhibitor competition. In vivo, selective degradation was observed starting at a dose as low as 1x10-4 mg/kg. This work established a strategy for PSMA targeted delivery of degraders, expanding their potential for clinical applications.