Exploring AR-NFkappaB/p52-Targeted Inhibitors as Novel Therapy Against Castration-Resistant Prostate Cancer Progression

摘要

The goal of this research was to verify the specificity of the inhibition of androgen receptor (AR) NFkB/p52 interaction by small molecule AR/p52 inhibitors (selected from prior high throughput screen) in cell culture and AR/p52 activity assays, and determine the efficacy of the compounds against castration resistant prostate cancer (CRPCa) cell / xenograft growth. Data from this research should establish the AR-p52 interaction as a viable new target for preventing progression to CRPCa and identify lead compound(s) to be further developed for preclinical toxicity testing and clinical trials for PCa that fall beyond the scope of this proposal. Cell culture studies identified a lead compound with IC50 of 5 M against both androgen-dependent and independent PCa cell growth that involves reduction in CyclinD1, and significant inhibition of AR transcriptional activity as measured by PSA mRNA as well as inhibition of AR and p52 translocation to nucleus. Efficacy of the lead compound in an oral regimen against CRPCa xenograft tumor development and progression was established. Thus the lead compound shows evidence of specificity for AR-p52 interaction and efficacy against CRPCa. These data help establish AR-p52 interaction as a viable new target for PCa therapy and identify a lead compound that can be further developed toward clinical application as a new therapeutic agent to prevent progression of CRPCa.