Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors.

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Androgen receptor (AR) mutations drive resistance to anti-androgen drugs in prostate cancer.
• Conventional anti-AR drugs target the androgen binding site (ABS), which is prone to resistance mutations.
• Inhibitors targeting the AR DNA-binding domain (AR-DBD) offer a novel therapeutic strategy.

Purpose of the Study:

• To develop novel AR-DBD inhibitors for prostate cancer treatment.
• To investigate the molecular basis of cross-reactivity between AR-DBD inhibitors and the AR ABS.
• To design AR-DBD inhibitors that avoid cross-reactivity with the AR ABS.

Main Methods:

• Synthesis and screening of 4-(4-phenylthiazol-2-yl)morpholine derivatives as AR-DBD inhibitors.
• Co-crystallization of the T878A mutated AR ligand-binding domain (LBD) with VPC14368.
• Computational modeling to elucidate the structural basis of VPC14368's agonistic effect.

Main Results:

• Wild-type AR was effectively suppressed by many AR-DBD inhibitors.
• VPC14368 exhibited partial agonism toward the mutated T878A AR, indicating cross-reactivity with the AR ABS.
• Structural analysis revealed that helix 12 shifts upon VPC14368 binding, causing agonistic behavior.

Conclusions:

• AR-DBD inhibitors represent a promising approach for overcoming anti-androgen drug resistance in prostate cancer.
• Understanding the structural basis of cross-reactivity is crucial for designing effective AR-targeted therapies.
• Modified VPC14368 derivatives successfully eliminated cross-reactivity with the AR ABS while retaining AR-DBD inhibitory potency.