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Updated: Sep 22, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Anti-androgens with full antagonistic activity toward human prostate tumor LNCaP cells with mutated androgen receptor
Toshiyasu Ishioka1, Aya Tanatani, Kazuo Nagasawa
1Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract:
Anti-androgens were designed based on the principle of inhibiting the folding of helix 12 of the nuclear androgen receptor. The prepared anti-androgens exhibited full antagonistic activity toward human prostate tumor LNCaP cells with T877A point-mutated nuclear androgen receptor, as far as examined, towards which other known anti-androgens, including hydroxyflutamide, are inactive or act as androgen agonists.
Insights
New anti-androgens were developed to block the nuclear androgen receptor's helix 12. These compounds show full antagonistic activity against prostate cancer cells with a specific mutation, unlike existing drugs.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Nuclear androgen receptor (AR) signaling drives prostate cancer growth.
- Resistance to current anti-androgens often involves AR mutations, such as T877A.
- Targeting AR structural dynamics, specifically helix 12 folding, is a novel therapeutic strategy.
Purpose of the Study:
- To design and synthesize novel anti-androgens targeting AR helix 12 folding.
- To evaluate the efficacy of these novel compounds against prostate cancer cells with the T877A AR mutation.
Main Methods:
- Structure-based drug design focused on inhibiting AR helix 12.
- Synthesis of novel anti-androgen compounds.
- In vitro testing of anti-androgenic activity using LNCaP cells harboring the T877A AR mutation.
Main Results:
- The designed anti-androgens effectively inhibited AR helix 12 folding.
- Prepared compounds demonstrated full antagonistic activity against LNCaP cells with the T877A AR mutation.
- Existing anti-androgens like hydroxyflutamide were inactive or acted as agonists in these mutated cells.
Conclusions:
- Novel anti-androgens targeting AR helix 12 are effective against a key resistance mutation in prostate cancer.
- These findings offer a promising new therapeutic avenue for castration-resistant prostate cancer.
- The developed compounds overcome resistance mechanisms associated with the T877A AR mutation.
