title: 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.
abstract: Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After 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. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of 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. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. Yamaoka_Masuo@takeda.co.jp
authors.forename: Masuo
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.forename: Takenori
authors.initials: T
authors.lastname: Hitaka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaku
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Junzo
authors.initials: J
authors.lastname: Takahashi
authors.forename: Satoru
authors.initials: S
authors.lastname: Asahi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tasaka
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
mesh_terms: D000311:Adrenal Glands / Q000166:cytology* / Q000187:drug effects; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000037:antagonists & inhibitors / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000097:blood; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D009281:Naphthalenes / Q000097:blood / Q000494:pharmacology*; D009919:Orchiectomy; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013256:Steroids / Q000097:blood* / Q000378:metabolism*; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D013256:Steroids; D013739:Testosterone; D003687:Dehydroepiandrosterone; D013254:Steroid 17-alpha-Hydroxylase; D007654:Ketoconazole; C571806:orteronel; D006854:Hydrocortisone