Targeting androgen receptor degradation with PROTACs from bench to bedside - 13/01/23
Abstract |
Inhibition of androgen receptor (AR) has been extensively investigated to treat prostate cancer. Resistance mechanisms such as increased levels of androgen production, increased AR gene, enhancer expression and AR point mutations always reduce the clinical efficacy. Design and discovery of small-molecule PROTAC AR degraders have been pursued as a new therapeutic strategy to overcome common resistance mechanisms developed during prostate cancer treatment. In the last two decades, potent and efficacious PROTAC AR degraders have been gotten rapid development and several such compounds have been advanced into preclinical phase and phase I/II trials for the treatment of human prostate cancers. Especially, the first PROTAC to enter the clinic, ARV-110, has shown good clinical effects in patients with mCRPC. This fully demonstrates the high clinical value of PROTAC strategy in treatment of human diseases. Here, we summarized the recent advances in the development of these potential clinical-stage PROTAC AR degraders.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | AR is a clinically fully validated target for treatment of human prostate cancer. |
• | PROTAC AR degraders overcome common resistance mechanisms developed during prostate cancer treatment with AR antagonists. |
• | Good progress of AR degraders in Phase I/II fully demonstrates the highly clinical value of PROTAC strategy in treatment of human diseases. |
• | Compounds with well-balanced physiochemical properties, like lower M.W. (∼800), good ClogP, ideal tPSA etc, are needed to be discovered to make them more orally bioavailable. |
Abbreviations : AR, PROTACs, mCRPC, UPS, SNIPERs, MDM2, IAP, CRBN, VHL, POI, DHT, FDA, ER, cIAP1, Dmax, DC50, Cmax, PK, PDX
Keywords : Androgen receptor (AR), Proteolysis targeting chimeras (PROTACs), Metastatic castration resistant prostate cancer (mCRPC), Drug resistance
Plan
Vol 158
Article 114112- février 2023 Retour au numéro
Article précédent
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