Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer

Area of Science:

• Biochemistry
• Drug Discovery
• Oncology

Background:

• Androgen receptor (AR) signaling drives lethal castration-resistant prostate cancer (CRPC).
• Classical AR antagonists face drug resistance challenges in CRPC treatment.
• Induced protein degradation presents a complementary therapeutic strategy.

Purpose of the Study:

• To review recent advancements in androgen receptor degraders for CRPC since 2020.
• To highlight novel degradation strategies and emerging AR degraders.
• To provide an updated overview of this therapeutic paradigm.

Main Methods:

• Review of proteolysis-targeting chimeras (PROTACs).
• Analysis of monomeric degraders, hydrophobic tagging, molecular glues, and autophagic degradation.
• Examination of clinical trial progress for AR degraders.

Main Results:

• Multiple AR degradation strategies show efficacy in downregulating AR.
• Six PROTACs and two monomeric AR degraders have entered Phase I/II clinical trials.
• Recent progress indicates significant potential for AR degraders in CRPC therapy.

Conclusions:

• Induced protein degradation is a promising approach for CRPC.
• AR degraders offer a distinct mechanism to overcome resistance to current therapies.
• Continued research into novel AR degraders is crucial for advancing CRPC treatment.