An androgen receptor N-terminal domain antagonist for treating prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Advanced prostate cancer treatments targeting the androgen receptor (AR) ligand-binding domain (LBD) often fail, leading to lethal castration-resistant prostate cancer (CRPC).
• The AR N-terminal domain (NTD) is crucial for AR activity, but its intrinsic disorder complicates targeted inhibition.
• Constitutively active AR splice variants lacking the LBD are implicated in CRPC progression.

Purpose of the Study:

• To investigate EPI-001, a novel small-molecule antagonist targeting the AR NTD.
• To evaluate the efficacy of EPI analogs in inhibiting AR transcriptional activity and CRPC xenograft growth.

Main Methods:

• Investigated EPI-001, a small-molecule antagonist designed to inhibit protein-protein interactions within the AR NTD.
• Assessed the covalent binding of EPI analogs to the AR NTD.
• Evaluated the inhibition of transcriptional activity of both full-length AR and its splice variants.
• Tested the efficacy of EPI analogs in reducing the growth of CRPC xenografts in vivo.

Main Results:

• EPI analogs were found to covalently bind to the AR NTD.
• This covalent binding effectively blocked the transcriptional activity of AR and its splice variants.
• Treatment with EPI analogs significantly reduced the growth of CRPC xenografts.

Conclusions:

• Small-molecule inhibitors that covalently bind to intrinsically disordered proteins, such as the AR NTD, represent a promising therapeutic strategy.
• This approach offers potential for developing specific and effective anticancer agents for CRPC.
• Targeting the AR NTD provides a novel avenue for overcoming resistance to current hormone therapies.