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Avan Navaz Colah, Pharmsci graduate student (Ricke Lab), will be defending her PhD research thesis:

Overcoming therapeutic resistance: An integrative evaluation of crystal-engineered androgen receptor ligands through structural, molecular, and mechanistic profiling

Abstract:

Prostate cancer (PCa) is a major contributor to health burden in aging males and castration resistant prostate cancer (CRPC) is an advanced disease stage that develops through dysregulation of androgen receptor (AR) signaling. Despite therapeutic advances, long-term efficacy for many CRPC cases remains elusive. Androgen receptor ligand binding domain (AR LBD) point mutations are increasingly recognized as a mechanism of therapeutic resistance, inducing molecular changes that permit helix 12 closure even in the presence of inhibitory ligands and effectively converting AR pathway inhibitors (ARPIs) into agonists. As a result, these therapeutics exacerbate disease progression rather than serving as a curative measure. Therefore, there is a critical need for novel AR antagonists capable of circumventing these resistance mechanisms.

This study investigates a class of tetra-aryl cyclobutanes (CBs) as structurally and mechanistically distinct AR antagonists. Using crystal engineering and solid-state [2+2] photodimerization, we expanded the CB class through strategic derivatization, producing an established chlorinated CB (ClCB) and a newly derived brominated CB (BrCB). This synthesis step is atom-economical, solvent-free, byproduct-free, and yields quantitatively pure product. Inherently sustainable features, like those of the CB photodimerization, are a quality that is an increasingly important priority in pharmaceutical development.

Using in vitro and in silico models of AR point mutation, we defined the structure-function relationships, mechanism of action, and ligand-receptor interactions of both compounds. ClCB and BrCB demonstrated pan-inhibitory capacity across AR LBD point mutant subtypes, dose-dependent AR inhibition, blockade of nuclear internalization, and disruption of AR-mediated transcriptional activity, confirming the pharmacological relevance of the CB scaffold. Most notably, CBs exhibited resilience to AR LBD point mutation and were able to maintain antagonistic functionality even after undergoing significant changes in their ligand binding orientation. This is a key advantage over traditional ARPIs which are prone to therapeutic failure under such conditions.

CBs also demonstrated a cytostatic rather than cytotoxic mechanism of action, slowing CRPC cell growth and suppressing cell cycle progression — evidenced by reduced expression of cell cycle markers CDC20 and UBE2C — without directly reducing cell viability. This profile may confer a more favorable systemic side effect profile relative to conventional ARPIs, with potential implications for patient quality of life.

Global proteomic analysis revealed that CBs broadly recapitulate the proteomic response induced by conventional AR signaling inhibitors in CRPC models. Molecular docking further identified opportunities for structure-activity relationship-guided optimization at the ortho and para positions of the CB phenyl ring to improve binding affinity and selectivity. Together, these findings establish CBs as a promising therapeutic framework for CRPC, particularly where traditional ARPIs have failed.