Developing small molecule inhibitors that target androgen receptor signaling in castration-resistant prostate cancer

The transcription factor, androgen receptor (AR) is a key driver and plays an important role in prostate cancer. Androgen ablation therapy and brachytherapy remains the standard treatment of advanced prostate cancer, but unfortunately, it is not curative, and eventually the disease returns as lethal castration-resistant prostate cancer (CRPC). Previously we have reported that Urolithin A (Uro A), a natural compound, inhibits AR signaling and suppresses the growth of CRPC. Now, we have developed a series of pro-drug conjugates of Uro A and our initial structure-activity relationship (SAR) studies led to the identification of three small molecules as lead compounds. Hence, we investigated the effects of all three compounds and dissected their molecular mechanism in cell culture and mouse models of CRPC. All the three compounds more effectively inhibited the growth CRPC cell lines than the parent compound Uro A. Based on their IC 50 concentration; we identified a novel compound (ASR-600) that demonstrated better efficacy by inhibiting AR signaling in CRPC cell lines than the parental compound Uro A. The model system and molecular dynamics (MD) stimulation studies suggest that ASR600 bind to the ligand-binding domains of AR and blocks the conformation changes, that allows AR to phosphorylate and degrade in the cytosol. Further, our thermal shift assay confirmed ASR 600 binds to AR in presence and absence of Dihydrotestostreone. Our ongoing in vivo studies, may suggest whether oral administration of ASR-600 effectively inhibits the tumor growth raised from CRPC cell lines (C4-2B, 22RV1 and enzalutamide resistance C4-2B) in xenografted mice. These observations provide a rationale for devising novel therapeutic agent based on ASR 600 for the treatment of CRPC Citation Format: Balaji Chandrasekaran, Ashish Tyagi, Venkatesh Kolluru, Aakash M. Vadhanam, Becca von Baby, Suresh Gorle, Suman Sirimulla, Srinivasa R. Ramisetti, Arun K. Sharma, Murali K Ankem, Chendil damodaran. Developing small molecule inhibitors that target androgen receptor signaling in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2598.