Overcoming Resistance in the Androgen Receptor: Rational and Strategic Design of Advanced Antagonists

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Prostate cancer (PCa) relies on androgen receptor (AR) signaling.
• Current AR antagonists target the ligand binding pocket (LBP) but face resistance.
• Resistance mechanisms include AR mutations, amplification, and splice variants.

Purpose of the Study:

• To elucidate AR conformational regulation mechanisms.
• To design and develop novel AR antagonists overcoming resistance.
• To explore non-LBP mediated AR antagonism strategies.

Main Methods:

• Molecular dynamic (MD) simulations to understand AR conformational changes.
• Structure-based virtual screening (SBVS) and biological evaluation to identify lead compounds.
• Exploration of allosteric sites, novel binding pockets, and alternative domains for AR antagonism.

Main Results:

• MD studies provided atomic-level insights into AR conformational regulation.
• Identified potent lead compounds targeting LBP effective against AR mutations (F877L, W742C, T878A, H875Y).
• Developed first-in-class antagonists targeting the Dimerization Interface Pocket (DIP) for AR LBD dimerization inhibition.

Conclusions:

• Novel AR antagonists targeting LBP and non-LBP sites demonstrate potential against resistant PCa.
• Computational approaches are powerful tools for resistance-targeting drug discovery.
• A diverse pipeline of AR antagonists addresses unmet needs in advanced PCa treatment.