Exploiting Ligand-binding Domain Dimerization for Development of Novel Androgen Receptor Inhibitors.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Current androgen receptor (AR) antagonists target the ligand-binding pocket, leading to resistance in prostate cancer.
• AR-dependent mechanisms often drive tumor progression in resistant stages.
• Novel therapeutic strategies are needed to overcome AR inhibitor resistance.

Purpose of the Study:

• To identify novel AR inhibitors by targeting the AR ligand-binding domain (LBD) dimerization interface.
• To discover and characterize compounds that inhibit AR dimerization and transactivation.
• To evaluate the efficacy of these novel compounds in prostate cancer models.

Main Methods:

• In silico screening utilizing structural information of the AR LBD dimerization interface.
• Identification of a novel binding site, the Dimerisation Inhibiting Molecules (DIM) pocket.
• Virtual screening to select compounds targeting the DIM pocket, leading to the DIM20 family.
• Biolayer interferometry to confirm LBD binding and assess interaction with existing inhibitors.
• Cell proliferation assays using AR-positive and AR-negative prostate cancer cell lines.

Main Results:

• A novel DIM pocket at the AR LBD dimerization interface was identified.
• The DIM20 family of compounds was identified, inhibiting AR transactivation and dimerization.
• DIM20 compounds bind reversibly to the LBD and act noncompetitively with DHT.
• DIM20 and DIM20.39 specifically inhibit proliferation of AR-positive prostate cancer cells.
• Synergistic antiproliferative effects were observed when DIM compounds were combined with enzalutamide.

Conclusions:

• The DIM pocket represents a novel target for AR inhibition.
• DIM20 compounds offer a new therapeutic approach for prostate cancer, including resistant forms.
• Targeting AR dimerization provides a distinct mechanism to overcome treatment resistance and enhance efficacy.