The development and progression of prostate cancer is known to be dependent on androgens and their signaling mediated by the androgen receptor (AR). The primary therapeutic intervention involves using agents that lower serum testosterone (e.g., LHRH agonists), often in concert with an AR antagonist, such as bicalutamide. Despite a favorable initial anti-tumor response, most patients progress to the advanced hormone-refractory disease. The development of resistance to anti-androgen therapy has been shown to be associated with an increase in the levels of both AR mRNA and protein. This observation supports the concept that an AR antagonist with a significant improvement in potency as compared to bicalutamide and a broader spectrum of in vivo anti-tumor activity, including the bicalutamide-refractory human prostate tumor xenografts, may provide a significant clinical advantage in the treatment of advanced prostate cancer. This presentation will describe structure-activity relationships in a novel tetracyclic series of androgen receptor antagonists leading up to the identification of BMS-779333. It is a potent AR full antagonist, which exhibited broad spectrum efficacy in four human prostate tumor xenograft models. BMS-779333 did not exhibit agonist activity for AR mutant isoforms. Tumors that failed bicalutamide treatment were shown to retain their sensitivity to respond to BMS-779333. Transcriptomic changes in LuCaP-35 tumors treated with BMS-779333 were closer to castration than with other drug treatments. Based on its overall profile, BMS-779333 was selected for further preclinical evaluation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5782.