Molecules targeting the androgen receptor (AR) signaling axis beyond the AR-Ligand binding domain

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Prostate cancer (PCa) is a leading cause of cancer mortality in men.
• The androgen receptor (AR) pathway is crucial for PCa initiation and progression.
• Current PCa drugs target the AR's ligand-binding domain (LBD), but novel approaches are needed.

Purpose of the Study:

• To review emerging molecules targeting the AR's DNA-binding domain (DBD) and transactivation domain (TAD).
• To discuss compounds that modulate AR signaling through direct or indirect interactions with AR-TAD or AR-DBD.
• To highlight the therapeutic potential and limitations of these novel agents for PCa.

Main Methods:

• Literature review of compounds targeting AR-TAD and AR-DBD.
• Analysis of in vitro and in vivo data for discussed molecules.
• Comprehensive discussion of drug candidates and their mechanisms.

Main Results:

• Several classes of compounds show promise in targeting AR-TAD and AR-DBD.
• These include hairpin polyamides, niclosamide, EPI compounds, mahanine, VPC compounds, JN compounds, and BET inhibitors.
• Significant in vitro and in vivo data exist for these agents, demonstrating their potential.

Conclusions:

• Novel therapeutic strategies targeting the AR-DBD and AR-TAD are under development for prostate cancer.
• These agents offer alternative mechanisms to overcome resistance to LBD-targeting drugs.
• Further research and development are warranted to translate these findings into effective PCa therapies.