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Targeting androgen receptor degradation with PROTACs from bench to bedside

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.

 

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The inhibition of androgen receptor (AR) has been a major therapeutic target for the treatment of prostate cancer. However, resistance mechanisms such as increased androgen production, increased AR gene and enhancer expression, and AR point mutations have reduced the clinical efficacy of these therapies. To address these challenges, small-molecule PROTAC AR degraders have been developed as a new therapeutic strategy.

In the last two decades, significant progress has been made in the design and discovery of potent and efficacious PROTAC AR degraders. Several compounds have been advanced into preclinical and clinical trials for the treatment of human prostate cancer. Notably, ARV-110, the first PROTAC to enter the clinic, has shown promising clinical effects in patients with metastatic castration-resistant prostate cancer (mCRPC).

The success of these PROTAC AR degraders highlights their potential clinical value in the treatment of human diseases. This article summarizes recent advances in the development of potential clinical-stage PROTAC AR degraders, highlighting their potential to overcome resistance mechanisms and improve the efficacy of current prostate cancer therapies.

Related Products

Cat.No. Product Name Information
S6965 Bavdegalutamide (ARV-110) Bavdegalutamide (ARV-110) is an orally bioavailable, specific androgen receptor (AR) PROTAC degrader that leads to ubiquitination and degradation of AR. ARV-110 completely degrades androgen receptor (AR) in all cell lines tested with DC50 of < 1 nM. ARV-110 can be used for the research of prostate cancer.

Related Targets

Androgen Receptor