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bioRxiv · 10.1101/2024.04.25.591100

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

Meng, X.·Hu, X.·Zhang, S.·Wang, X.·Ma, S.·Qin, C.
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Abstract

PROTACs, degrading target protein to treat diseases, represent a highly promising drug design strategy. However, the degradation of target proteins by PROTACs in non-disease tissues may lead to systemic toxicity. Herein, capitalizing on the characteristic overexpression of PSMA in prostate cancer tumor tissues, we devised a PSMA-guided PROTACs specific targeting to prostate cancer. By conjugating 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 PROTAC molecules selectively degraded target proteins in PSMA-overexpressing prostate cancer cells, without affecting target proteins in non-PSMA-overexpressing cells. In vivo studies revealed that compared to conventional PROTACs, PSMA-guided PROTACs enhanced drug exposure in prostate cancer tumor tissues, prolonged half-life, and consequently achieved stronger and more sustained therapeutic effects. The PSMA-guided PROTAC strategy provides a novel avenue for disease tissue-specific PROTAC research, holding significant implications for targeted therapy in prostate cancer.

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Meng, X., Hu, X., Zhang, S., Wang, X., Ma, S., Qin, C.. 2024-04-26. PSMA-Guided PROTAC Degraders for Tumor-Specific Protein Degradation in Prostate Cancer. https://doi.org/10.1101/2024.04.25.591100

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