Abstract
Abstract Cytochrome P450 17α-hydroxylase/C17,20-lyase (CYP17) is a key enzyme in androgen bio-synthesis in adrenals and testes. It has been validated clinically as an effective target for CRPC through successful clinical trials with abiraterone acetate. Abiraterone acetate is a selective, potent inhibitor of Cyp17, and was recently approved as a treatment for CRPC. We have designed a novel Cyp17 inhibitor, BMN680, with improved pharmacokinetic (PK) profile and oral bioavailability while maintaining potent Cyp17 inhibition. BMN680 inhibits Cyp17 lyase activity with IC50 of 0.8 nM and reduces testosterone production in human adrenal cancer cell line H295R cells with IC50 of 3.87 nM. in vitro metabolic stability studies indicate that BMN680 has a half-life of 5-hr in human liver microsome and 8-hr half-life in human hepatocytes. Animal PK profiling in rats and monkeys demonstrated BMN680 has in vivo half-life of >4 hr and oral bioavailability of >30%. Single oral dosing of BMN680 at 10 mg/kg in normal, intact, Cynomolgus monkeys resulted in suppression of plasma testosterone level for up to 24 hour. Pharmacodynamic (PD) effect of single and multi-day oral dosing of BMN680 in monkey will be presented. In human liver microsome Cyp panel screen, BMN680 exhibited IC50 greater than 1.5 uM for all Cyp enzymes tested including 1A2, 2C9, 2C19, 2D6, 3A4, indicating low potential of drug-drug interaction. In conclusion, BMN680 is a potent Cyp17 inhibitor with low interaction with Cyp450 isoforms, and desirable PK and oral bioavailability. BMN680 can effectively suppress testosterone production in vivo, and will be further evaluated in preclinical development. Citation Format: Ying Feng, Bing Wang, Daniel Chu, Leonard Post, Yuqiao Shen. A novel, potent, Cyp17 inhibitor with favorable pharmacokinetics and oral bioavailability for potential treatment of human castration resistant prostate cancer (CRPC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2049. doi:10.1158/1538-7445.AM2013-2049
Published Version
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