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.