Castrate-resistant prostate cancer (CRPC) continues to be dependent on the androgen receptor (AR) for disease progression. We have synthesized and evaluated a novel compound that is a conjugate of colchicine and an AR antagonist (cyanonilutamide) designed to inhibit AR function in CRPC. A problem in multifunctional AR-binding compounds is steric hindrance of binding to the embedded hydrophobic AR ligand-binding pocket. Despite the bulky side chain projecting off of the AR-binding moiety, this novel conjugate of colchicine and cyanonilutamide binds to AR with a Ki of 449 nmol/L. Structural modeling of this compound in the AR ligand-binding domain using a combination of rational docking, molecular dynamics, and steered molecular dynamics simulations reveals a basis for how this compound, which has a rigid alkyne linker, is able to bind to AR. Surprisingly, we found that this compound also binds to tubulin and inhibits tubulin function to a greater degree than colchicine itself. The tubulin-inhibiting activity of this compound increases cytoplasmic AR levels in prostate cancer cells. Finally, we found that this compound has greater toxicity against androgen-independent prostate cancer cells than the combination of colchicine and nilutamide. Together, these data point to several ways of inhibiting AR function in CRPC.
ASJC Scopus subject areas
- Cancer Research