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.

Automated summary

Inhibition of androgen receptor (AR) has been extensively studied for treating prostate cancer, but resistance mechanisms limit its efficacy. Small-molecule PROTAC AR degraders have emerged as a new therapeutic strategy to overcome resistance mechanisms. In the last two decades, potent PROTAC AR degraders have shown promising results in preclinical and clinical trials, with ARV-110 demonstrating good clinical effects in patients with mCRPC. This highlights the high clinical value of PROTAC strategy in treating human diseases. This review summarizes the recent advances in the development of potential clinical-stage PROTAC AR degraders.