CYP17 inhibitors for prostate cancer therapy

Abstract

Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels.Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development.

Phase I/II Trial of Orteronel (TAK-700)—an Investigational 17,20-Lyase Inhibitor—in Patients with Metastatic Castration-Resistant Prostate Cancer

“…These findings have fostered an interest in CYP17A1 inhibition to deplete both intratumoral and extragonadal sources of steroid ligands (6,7). CYP17A1 is an essential enzyme for biosynthesis/production of steroidal hormones, and has both 17,20-lyase and 17a-hydroxylase activities (8)(9)(10). This pathway's importance in CRPC has been reinforced by positive phase III trials with abiraterone acetate (Zytiga; refs.…”

Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

“…Although type II ligands are typically viewed as P450 inhibitors due to stabilization of the low spin-state via coordination of the heme-iron to an aromatic nitrogen [69,82,83], studies have shown that in general, type II binding ligands have a higher affinity for the active site than similar but nitrogen-lacking substrates [84][85][86]. Moreover, a number of reports have demonstrated that P450s such as P450 3A4 can metabolize type II ligands, and in some cases to a greater extent than related type I ligand analogues [84,[87][88][89][90][91].…”

Cytochromes P450: Roles in Diseases

“…Inhibition of the lyase activ- ity that leads to reduced androgen synthesis inhibits testosterone production and therefore the development of prostate cancer. Drugs that are effective in inhibition of CYP17A1 have been developed (21,22). Now that the enzyme structure cocrystallized with such inhibitors is available (17), even better drugs that would be able to inhibit the lyase activity without an effect on hydroxylase activity could probably be designed.…”