Abstract DD01-03: TAK-700, an inhibitor of 17,20-lyase
Authors: Masuo Yamaoka, Takahito Hara, Hiroshi Miki, Takenori Hitaka, Tomohiro Kaku, Naohiro Kawaguchi, Hitomi Yamasaki, Toshiyuki Takeuchi, Akihiro Tasaka, Masami Kusaka
Journal: Cancer Research (2010)

Abstract Background: Recent studies suggest that residual adrenal androgen after castration could be responsible for the progression of castration-resistant prostate cancer (CRPC). To develop an effective therapy for CRPC that inhibits the production of adrenal and testicular androgens, we searched for a novel, non-steroidal, selective, and potent inhibitor of 17,20-lyase, a key enzyme in androgen synthesis, and identified TAK-700 as a clinical candidate. Methods: Enzyme assay was conducted using radiolabeled substrates. The enzyme reaction products were separated by thin layer chromatography and the radioactivity was measured by a bio-image analyzer. We assessed the activity and specificity of TAK-700 on androgen production in vitro in monkey adrenal cells and human adrenocortical tumor cell line, using a radioimmunoassay. Using a single dose of [14C]TAK-700 1 mg/kg, we investigated the pharmacokinetics and bioavailability of TAK-700 in cynomolgus monkeys, and assessed the effects of TAK-700 7.5 and 15 mg/kg twice daily (BID) for 7 days on serum androgen levels in castrated and intact cynomolgus monkeys. Results: TAK-700 potently inhibited the activities of human and monkey 17, 20-lyase (CYP17A1) with IC50 values of 140 and 27nmol/L, respectively. The inhibitory activity of TAK-700 on 17-hydroxylase was lower than that on 17, 20-lyase in all the enzyme preparations. IC50 values of ketoconazole and abiraterone for human 17, 20-lyase were 110 and 27nmol/L, respectively. TAK-700 did not inhibit monkey 11-hydroxylase up to 10μmol/L. In addition, IC50 values of TAK-700 for all CYP-specific activities (drug-metabolizing enzymes) examined were higher than 10 μmol/L. TAK-700 suppressed the production of DHEA, androstenedione, cortisol, corticosterone and aldosterone by monkey adrenal cells with IC50 values of 110, 130, 310, &amp;gt;100,000 and 4,400nmol/L, respectively. The IC50 value for cortisol production was only 3-fold higher than that for DHEA production in monkeys, reflecting low specificity of inhibition between monkey 17, 20-lyase and 17-hydroxylase activity (IC50 values: 27 vs 38nmol/L). Ketoconazole suppressed the production of DHEA, androstenedione, cortisol, corticosterone and aldosterone by monkey adrenal cells with IC50 values of 340, 580, 340, 1,500 and 350nmol/L, respectively. TAK-700 inhibited the production of dehydroepiandrosterone (DHEA) and cortisol in human adrenocortical tumor line NCI-H295R cells with IC50 values of 37 and 990nmol/L, respectively, showing about 27-fold selectivity for DHEA production. Ketoconazole inhibited the production of DHEA and cortisol with IC50 values of 330 and 480nmol/L (selectivity 1.5-fold), respectively, and abiraterone inhibited the production of DHEA and cortisol with IC50 values of 2.7 and 23nmol/L (selectivity: 8.5-fold), respectively. TAK-700 showed the highest specificity of inhibition for DHEA production among these 3 compounds. After oral administration of [14C]TAK-700 1 mg/kg, maximum plasma concentration (Cmax) was 0.147 μg/mL, time to Cmax (Tmax) was 1.7 hours, elimination half-life (t1/2) was 3.8 hours, and exposure (area under the plasma concentration-time curve in 24 hours, AUC0-24h) was 0.727 μg·h/mL. Oral bioavailability of TAK-700 in monkeys was 70.5%. Oral dosing of TAK-700 7.5 and 15 mg/kg BID rapidly (within 1 day) suppressed serum levels of the androgens dehydroepiandrosterone (DHEA) and testosterone and of cortisol in both castrated and gonadally intact monkeys. While suppression of DHEA and cortisol levels persisted during the 7-day treatment period in castrated monkeys, suppression of testosterone was attenuated from the second day of treatment, possibly due to activation of the hypothalamus-pituitary-gonad axis. TAK-700 had a milder suppressive effect on cortisol levels than on DHEA levels. During the treatment period, mean DHEA levels decreased to 9.0% and 6.9% of baseline levels in castrated monkeys treated with TAK-700 7.5 and 15 mg/kg, respectively. The mean cortisol levels decreased to 26.0% and 17.3% of baseline levels with TAK-700 7.5 and 15 mg/kg, respectively. In vitro results have shown that the specificity of TAK-700 suppression of DHEA production over cortisol production is 10-fold greater in human adrenal-origin cells than in monkey adrenal cells. Therefore, the impact of TAK-700 on human serum cortisol levels may be smaller than that in monkeys. Conclusion: As TAK-700 potently and selectively inhibited 17, 20-lyase activity and DHEA production by H295R cells and suppressed serum androgen levels in castrated monkeys, TAK-700 may be effective for at least some types of CRPC, and clinical evaluation of TAK-700 is now underway in patients with CRPC. Citation Format: Masuo Yamaoka, Takahito Hara, Hiroshi Miki, Takenori Hitaka, Tomohiro Kaku, Naohiro Kawaguchi, Hitomi Yamasaki, Toshiyuki Takeuchi, Akihiro Tasaka, Masami Kusaka. TAK-700, an inhibitor of 17,20-lyase [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr DD01-03