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Updated: Jan 27, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer

Jiang Yu1, Lanxi Zhang1, Guoyi Yan2

  • 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.

European Journal of Medicinal Chemistry
|March 30, 2019
PubMed

Insights

A novel compound, 4a, derived from Abiraterone and Enzalutamide, shows potent activity against prostate cancer cells, including those resistant to Enzalutamide. This suggests compound 4a as a promising treatment for advanced prostate cancer.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Prostate cancer (PC) is a leading global malignancy in men.
  • Abiraterone Acetate and Enzalutamide are standard treatments for metastatic castration-resistant prostate cancer (mCRPC).
  • Emerging resistance to Enzalutamide necessitates the development of new therapeutic agents.

Purpose of the Study:

  • To design and synthesize novel nonsteroidal compounds by hybridizing Abiraterone and Enzalutamide.
  • To evaluate the efficacy of these new compounds as androgen receptor (AR) antagonists.
  • To identify a potential candidate for treating Enzalutamide-resistant prostate cancer.

Main Methods:

  • Synthesis of a new series of nonsteroidal compounds.
  • In vitro cell proliferation assays using VCaP and 22Rv1 cell lines.
  • Assessment of AR antagonist activity against wild-type and mutant AR.
  • Competitive binding assays to determine binding affinity to AR.

Main Results:

  • Compound 4a, featuring a diphenylamine scaffold, demonstrated potent and selective AR antagonism.
  • Compound 4a exhibited superior antiproliferative activity compared to Enzalutamide in AR-overexpressing and H874Y-mutated AR cells.
  • Compound 4a effectively inhibited AR-F876L mutants, conferring Enzalutamide resistance.
  • Compound 4a showed higher binding affinity to AR than Enzalutamide.

Conclusions:

  • Compound 4a is a potent AR antagonist with significant antiproliferative effects.
  • Compound 4a demonstrates efficacy against AR mutations associated with Enzalutamide resistance.
  • Compound 4a represents a promising therapeutic candidate for Enzalutamide-resistant prostate cancer.
Keywords:
Androgen receptor antagonistCastration-resistant prostate cancerEnzalutamide resistanceF876L mutation

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