PSMA-Guided PROTAC Degraders for Tumor-Specific Protein Degradation in Prostate Cancer

PROTACs that degrade target proteins to treat diseases represent a highly promising strategy in drug design. However, the degradation of target proteins in nondisease tissues may lead to systemic toxicity. Herein, capitalizing on the characteristic overexpression of PSMA in prostate cancer, we devised PSMA-guided PROTACs-specific targeting to prostate cancer. By conjugation of AR degraders and BET degraders separately with PSMA ligands via cleavable linkers, two classes of PSMA-guided PROTACs were obtained. In vitro experiments demonstrated that PSMA-guided PROTACs selectively degraded target proteins in PSMA-overexpressing prostate cancer cells without affecting target proteins in other cells. In vivo studies revealed that compared to conventional PROTACs, PSMA-guided PROTACs enhanced drug exposure in prostate cancer tissues and prolonged half-life and consequently achieved stronger and more sustained therapeutic effects. This work provides a novel avenue for disease tissue-specific PROTAC research, holding significant implications for targeted therapy in prostate cancer.