A novel steroidal antiandrogen targeting wild type and mutant androgen receptors

Area of Science:

• Oncology
• Endocrinology
• Medicinal Chemistry

Background:

• Prostate cancer (PCa) progression is driven by androgens, with antiandrogen therapy being an alternative to castration.
• Patients often relapse due to androgen receptor (AR) mutations that confer resistance to existing antiandrogens.
• Mutant ARs can exhibit agonistic activity with classical antagonists, leading to treatment failure.

Purpose of the Study:

• To synthesize and screen novel dihydrotestosterone (DHT)-derived compounds for antiandrogen activity.
• To evaluate the efficacy of these compounds against wild-type (WT) and mutant ARs.
• To identify a potent steroidal antiandrogen effective against resistant prostate cancer.

Main Methods:

• Synthesis and screening of 37 novel DHT derivatives.
• Luciferase reporter gene assays to determine antagonistic activity against WT and mutant ARs (T877A, W741C, W741L, H874Y).
• Assays for cellular proliferation and prostate-specific antigen (PSA) expression in LNCaP and 22Rv1 cells using crystal violet, real-time PCR, and Western blots.

Main Results:

• A novel compound, RB346, demonstrated potent antagonistic activity against all tested AR forms, including mutants.
• RB346 effectively prevented DHT-induced proliferation and PSA expression in PCa cell lines without agonistic activity.
• RB346 showed higher binding affinity for WT-AR, T877A-AR, and H874Y-AR compared to bicalutamide, which exhibited unfavorable agonistic activity for W741L-AR.

Conclusions:

• RB346 is the first potent steroidal antiandrogen effective against both wild-type and various mutant forms of the androgen receptor.
• RB346 represents a promising therapeutic candidate for overcoming antiandrogen resistance in advanced prostate cancer.
• The compound's lack of agonistic activity, even against mutated ARs, distinguishes it from existing treatments like bicalutamide.