Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Current androgen deprivation therapies target the AR C-terminal domain.
• The AR N-terminal domain (NTD) is crucial for transactivation but difficult to target directly due to its disordered structure.
• The cochaperone BAG1L interacts with the AR NTD, presenting a potential therapeutic target.

Purpose of the Study:

• To develop a novel androgen receptor (AR) inhibitor by targeting the AR NTD via its interaction with the cochaperone BAG1L.
• To identify small molecules that disrupt the BAG1L-AR NTD interaction.
• To evaluate the efficacy of identified compounds in inhibiting AR activity and prostate cancer cell proliferation.

Main Methods:

• Screening for small molecules that inhibit the BAG1L-AR NTD interaction.
• Characterization of the identified compound 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17).
• Assessment of A4B17's effects on AR NTD activity, AR target gene expression, and prostate cancer cell proliferation.

Main Results:

• Identification of A4B17, a small molecule that inhibits BAG1L-AR NTD interaction.
• A4B17 attenuates BAG1L-mediated AR NTD activity and downregulates AR target gene expression.
• A4B17 inhibits the proliferation of AR-positive prostate cancer cells.

Conclusions:

• A4B17 is a novel AR antagonist targeting the AR NTD through inhibition of the BAG1L interaction.
• This approach represents a new strategy for developing therapeutics against AR-positive prostate cancer.
• The identified compound serves as a prototype for future AR-targeted prostate cancer treatments.