ANDROGEN RECEPTOR REGULATION BY SMALL MOLECULE ENANTIOMERS

Smart overview of the Invention

A novel class of chiral compounds has been identified that exhibits unique effects on the androgen receptor (AR). The (R)-enantiomers function as classical anti-androgens, while the (S)-enantiomers activate AR signaling. This discovery highlights the duality of enantiomeric behavior, which is significant in the context of castration-resistant prostate cancer, where resistance to AR-targeted therapies often arises from mutations in the AR-ligand binding domain.

Challenges in Current Therapies

Existing small molecule therapies targeting AR are increasingly ineffective due to various resistance mechanisms, including mutations that convert antagonists into agonists. Enzalutamide is currently the only FDA-approved anti-androgen for metastatic castration-resistant prostate cancer (CRPC), emphasizing the need for new agents. Understanding how these structural changes affect drug efficacy is crucial for developing more effective treatments.

Research Methodology

The research involved a medicinal chemistry campaign focused on enhancing AR antagonism using BMS-641988 as a scaffold. Two lead compounds, EITM-1702 and EITM-1707, were identified for their ability to inhibit the growth of prostate cancer cells with mutant AR. Computational modeling indicated these compounds have a reduced likelihood of crossing the blood-brain barrier, which is advantageous for minimizing neurotoxicity associated with existing therapies.

Compound Formulation and Use

The disclosed compounds are represented by a specific formula and include various substituents that enhance their therapeutic potential. These compounds can be formulated into pharmaceutical compositions for treating cancers such as breast, lung, pancreatic, prostate, or colon cancer. The method involves administering an effective amount of these compounds to patients diagnosed with cancer.

Future Directions

The findings underscore the potential of these new chiral compounds as promising candidates for preclinical development in cancer therapy. The unique antagonist-agonist properties based solely on enantiomerism present an innovative approach to overcoming drug resistance in prostate cancer treatment and may lead to better safety profiles compared to current therapies.