Abstract C134: EN3356, a novel CYP17A inhibitor for the treatment of castration resistant prostate cancer

• Published in: Molecular cancer therapeutics Vol. 12; no. 11_Supplement; p. C134
• Main Authors: Laping, Nicholas J., Sivanandhan, Dhanalakshmi, Kethiri, Raghava Reddy, Dewang, Purushottam M., Vijayendra, Ajith, Zainuddin, Mohd, Mullangi, Ramesh, Rao, Niranjan, Venkatesan, Aranapakam M., Reddy, Sanjeeva, Gupta, Sandeep, Smith, Roger A.
• Format: Journal Article
• Language: English
• Published: 01.11.2013
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-C134

Abstract Androgens are a major driver of prostate cancer growth. As prostate cancer progresses, it can escape standard androgen deprivation therapy by relying on extra-testicular CYP17 enzyme activity for androgen synthesis. EN3356 is a novel non-steroidal CYP17 inhibitor that reduces androgen synthesis and is designed to treat castration-resistant prostate cancer. EN3356 provides potent inhibition of CYP17 lyase activity in rat and human testicular microsomes, and in human adrenocortical carcinoma H295R cells it also inhibits testosterone synthesis potently. In contrast to abiraterone, EN3356 is selective for inhibiting testosterone synthesis over cortisol synthesis. This finding suggests that EN3356 may not require co-administration of prednisone to mitigate mineralocorticoid excess. In pre-clinical studies, EN3356 exhibited high oral bioavailability. EN3356 inhibited serum testosterone levels in the rat and caused a robust decrease of seminal vesicle and prostate weights following 14-days of oral administration. GLP safety studies were completed in two preclinical species and identified a high safety margin. A combination Phase I/II study in metastatic castration-resistant prostate cancer is currently under initiation in the US and is anticipated to start enrolling subjects in the fourth quarter of 2013. Based on the potent inhibitory activity of EN3356 against CYP17 lyase in vitro, selective inhibition of testosterone synthesis versus cortisol synthesis, and robust weight reduction of androgen sensitive organs in vivo, EN3356 has the potential to be a selective and efficacious therapy for the treatment of castration-resistant prostate cancer. Disclosure: Funding for this research was provided by Endo Pharmaceuticals Inc. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C134. Citation Format: Nicholas J. Laping, Dhanalakshmi Sivanandhan, Raghava Reddy Kethiri, Purushottam M. Dewang, Ajith Vijayendra, Mohd Zainuddin, Ramesh Mullangi, Niranjan Rao, Aranapakam M. Venkatesan, Sanjeeva Reddy, Sandeep Gupta, Roger A. Smith. EN3356, a novel CYP17A inhibitor for the treatment of castration resistant prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C134.