Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Androgen receptor (AR) is a critical therapeutic target in prostate cancer (PCa).
• Hormone-sensitive prostate cancer (HSPC) and advanced PCa progression are AR-dependent.
• Targeting AR is crucial for effective PCa treatment strategies.

Purpose of the Study:

• To identify novel AR antagonists for prostate cancer treatment.
• To discover potent lead compounds through structure-based drug design.
• To develop new therapeutic strategies targeting AR-driven PCa.

Main Methods:

• Structure-based virtual screening using molecular docking and free energy calculations.
• Identification of a novel hit compound (C18) with anti-AR activity.
• Structure-activity relationship (SAR) analysis and structural optimization of C18.

Main Results:

• A novel hit compound (C18) with an IC50 of 2.4 μM against AR transcriptional activity was identified.
• Structural optimization led to the discovery of AT2, a more potent AR antagonist (16-fold improvement).
• AT2 effectively inhibited AR transcriptional function and nuclear translocation, similar to second-generation AR antagonists.

Conclusions:

• The identified AR antagonists, particularly AT2, show significant potential as lead compounds.
• These compounds could form the basis for developing novel therapeutics for AR-driven prostate cancer.
• Further development of these antagonists may lead to improved treatment options for PCa patients.