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A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives

Si Ha1, Guoshun Luo1, Hua Xiang1

  • 1State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China.

Journal of Medicinal Chemistry
|December 2, 2022
PubMed

Insights

New androgen receptor (AR) degraders offer promising treatments for castration-resistant prostate cancer (CRPC). This review details AR degraders, including PROTACs and SARDs, for CRPC therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Prostate cancer (PC) relies on androgen receptor (AR) signaling, a common malignancy in men.
  • Androgen deprivation therapy for PC often leads to castration-resistant prostate cancer (CRPC), where AR remains a key driver.
  • There is a critical need for novel therapeutic strategies to overcome CRPC resistance.

Purpose of the Study:

  • To comprehensively review small-molecule androgen receptor (AR) degraders for treating castration-resistant prostate cancer (CRPC).
  • To explore diverse mechanisms of AR degradation, including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), and hydrophobic tags (HyT).
  • To analyze structure-activity relationships, biomedical applications, and therapeutic potential of AR degraders.

Main Methods:

  • Literature review and synthesis of existing research on AR degraders.
  • Analysis of diverse AR degradation mechanisms and their chemical structures.
  • Evaluation of preclinical and clinical data on AR degradation-based therapeutics.

Main Results:

  • Small-molecule AR degraders, including PROTACs, SARDs, and HyT, demonstrate significant potential in targeting AR signaling in CRPC.
  • These agents exhibit varied mechanisms of action, offering new avenues for overcoming treatment resistance.
  • Structure-activity relationship studies provide insights into optimizing AR degrader efficacy and selectivity.

Conclusions:

  • AR degraders represent a promising therapeutic class for CRPC, addressing a significant unmet medical need.
  • Further development of AR degradation-based strategies holds potential for improved patient outcomes in advanced prostate cancer.
  • This review highlights the therapeutic value and future directions for AR degraders in CRPC treatment.

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