Inhibition Of The Androgen Receptor At Two Drug-Targetable Sites On The Dna-Binding Domain Protein Surface

The androgen receptor (AR) is a hormone inducible transcription factor that continues to be an important drug-target to prevent or slow the progression of prostate cancer. Current small molecule inhibitors, such as Enzalutamide (anti-androgens), compete with naturally occurring steroids that bind to the hormone binding pocket of the AR ligand binding domain (LBD). In advanced or castration resistant prostate cancer (CRPC), mutations in the LBD confer drug-resistance by converting anti-androgens into agonists, prompting research to develop small molecule inhibitors that target different sites on the AR protein surface. Recently, we characterized a set of small molecules that could interact with the DNA binding domain (DBD) of the AR and block its transcriptional activity. Here, we extend the pioneering observations by clarifying the mechanism of two classes of compounds that either block AR-chromatin interactions or reduce AR-dimerization in the cell nucleus. Compound efficacy is demonstrated across multiple prostate cancer cells lines, including enzalutamide resistant forms, with respect to AR transactivation, cell viability and expression of downstream genes. We also characterize the pharmacological properties of the lead compound and its effects on tumour xenografts in mice. Collectively, these results lay the foundation for the development of alternative prostate cancer drugs that interfere with the biochemical function of the activated, nuclear localized AR. Citation Format: Kush Dalal, Aishwariya Sharma, Mani Roshan-Moniri, Hendrik Borgmann, Nada Lallous, Shannon Awrey, Huifang Li, Fuqiang Ban, Eric LeBlanc, Artem Cherkasov, Paul S. Rennie. Inhibition of the androgen receptor at two drug-targetable sites on the DNA-binding domain protein surface. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4644.