Chapter 6: Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer

The etiology and progression of prostate cancer is dependent on androgens and their signaling, which is mediated by the androgen receptor (AR). Standard treatment for prostate carcinoma involves androgen depletion with luteinizing hormone-releasing hormone agonists, or surgical orchiectomy, often in concert with an anti-androgen, such as bicalutamide. After a favorable initial response, the tumors often evolve to regain their ability to grow despite low levels of circulating androgens. Recent studies have implicated elevated AR expression as the molecular cause of drug resistance and highlighted a need for more potent AR pan-antagonists. At Bristol-Myers Squibb, a structure-based design approach using a [2.2.1]-oxabicyclo-imide scaffold led to discovery of BMS-641988, which has 10-fold increased AR antagonist potency compared with bicalutamide. Importantly, BMS-641988 exhibited robust anti-tumor activity in tumors that failed bicalutamide treatment. However, BMS-641988 exhibited only a 5-fold safety margin against QT prolongation observed in telemetrized dogs. Significant variability was observed across species in the ratio of parent BMS-641988 to BMS-949, an active metabolite that caused convulsions in animals at high doses. A second active metabolite, BMS-511, was the primary species at steady-state in humans, but it was not observed in any preclinical studies. Development of BMS-641988 was halted due to unfavorable clinical findings on safety and efficacy. Further structural modifications yielded BMS-779333, a novel AR pan-antagonist with significantly improved cardiovascular and metabolic profiles compared to BMS-641988. It exhibited broad spectrum efficacy in four tumor xenograft models dependent on wild-type and/or mutant AR, and generated a transcriptomic profile resembling castration. However, further development was stopped after BMS-779333 induced seizures in dogs. Several important lessons can be gleaned from this research experience, including: 1) the necessity of navigating through an unpredictable and diverse set of liabilities that may not be related to the biological target, e.g. convulsions and QT prolongation and 2) increased investigation of active metabolites, especially when lead compounds suffer from severe toxicity without premonitory signs, such as seizure.