IC50: Orteronel inhibited monkey 17,20-lyase and 17-hydroxylase activities with IC50 values of 27 and 38 nmol/L, respectively [1].

Orteronel is an androgen biosynthesis inhibitor. It selectively inhibits the enzyme CYP17A1 which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity (http://en.wikipedia.org/wiki/Orteronel).

In vitro: Orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC50 value of orteronel for cortisol was about 3-fold higher than that for DHEA. Moreover, in human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys [1].

In vivo: After Orteronel single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC [1].

Clinical trial: Takeda Pharmaceutical Company Limited announced that it has voluntarily decided to end the development program for orteronel (TAK-700) for prostate cancer. The decision follows the results of two Phase 3 clinical trials in metastatic, castration resistant prostate cancer (mCRPC). The studies found while orteronel plus prednisone could extend the time patients lived before their cancer progressed, it did not extend overall survival in these patients. After careful consideration of the data from these trials, the company has determined that the drug has not demonstrated a clinical profile sufficient to move forward in mCRPC, given the availability of other therapies.

Reference:
[1] Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, Asahi S, Miki H, Tasaka A, Kusaka M. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012;129(3-5):115-28.