Novel Inhibitors of Protein-Protein Interaction for Prostate Cancer Therapy

摘要

The goal of this research was to firmly establish the mechanism of androgen receptor (AR)-JunD heterodimer induction of the SSAT gene leading to oxidative stress that contributes to the development and progression of prostate cancer (PCa), and to identify small molecules that specifically inhibit this AR-JunD interaction and prevent development/progression of PCa in preclinical models. Data from this research would identify the most efficacious drug to be further developed in preclinical toxicity testing and clinical trials for PCa that fall beyond the scope of this proposal. From this research it has been established that certain sequences of the SSAT promoter are important for androgen-induced SSAT activation, and that compounds that specifically inhibit the interaction of AR and JunD can block the AR-JunD ROS- generating pathway and inhibit growth in PCa cells. Furthermore, the lead AR- JunD inhibitor showed efficacy against the castrate-resistant C4-2 PCa xenograft model. However, lack of efficacy against androgen-dependent LNCaP and TRAMPxFVB transgenic PCa models suggests its application more for treatment of CRPCa than for chemopreventive or early-stage PCa therapy. Further preclinical animal efficacy studies are needed to support translation of the lead compound to clinical testing. Overall the data supports AR-JunD inhibitors as a new class of agents for further research and development as new therapies for early- stage recurrent PCa patients, who have no approved therapy and represent a long unmet medical need.