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CYP17 inhibitors—abiraterone, C17,20-lyase inhibitors and multi-targeting agents

Key Points

  • 17α-Hydroxylase/C17,20-lyase (CYP17) is a steroidogenic enzyme that is central to the production of androgens, and is targeted by abiraterone in men with castration-resistant prostate cancer

  • Abiraterone is a promiscuous drug, interacting with numerous targets that include CYP11B1 and a panel of hepatic CYP enzymes; these interactions explain the adverse effects profile of the drug

  • Furthermore, inhibition of the 17α-hydroxylase activity of CYP17 is responsible for the secondary mineralocorticoid excess observed in men taking abiraterone; selective C17,20-lyase inhibitors might avoid this effect

  • CYP17 inhibitors that interfere with the androgen receptor (AR) might enhance clinical benefit and might result in increased compliance and reduced risk of drug–drug interactions compared with combined regimens

  • Dual inhibitors of CYP17 and CYP11B1 might improve curative effects in patients with mutated ARs that are agonized by cortisol

  • Dual inhibitors that target the C17,20-lyase activity of CYP17 and CYP11B2 might reduce the risks of cardiovascular complications associated with abiraterone use by mitigating increases in aldosterone levels

Abstract

As the first in class steroid 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor, abiraterone acetate (of which the active metabolite is abiraterone) has been shown to improve overall survival in patients with castration-resistant prostate cancer (CRPC)—in those who are chemotherapy-naive and those previously treated with docetaxel. Furthermore, the clinical success of abiraterone demonstrated that CRPC, which has previously been regarded as an androgen-independent disease, is still driven, at least in part, by androgens. More importantly, abiraterone is a 'promiscuous' drug that interacts with a number of targets, which dictate its clinical benefits and adverse effects profile. Besides CYP17 inhibition, abiraterone acts as an antagonist to the androgen receptor and inhibits 3β-hydroxysteroid dehydrogenase—two effects that potentially contribute to its antitumour effects. However, the inhibition of the 17α-hydroxylase activity of CYP17, CYP11B1 and a panel of hepatic CYP enzymes leads to adverse effects and toxicities that include secondary mineralocorticoid excess. Abiraterone is also associated with increased incidence of cardiac disorders. Under such circumstances, development of new CYP17 inhibitors as an additional line of defence is urgently needed. To achieve enhanced clinical benefits, new strategies are being explored that include selective inhibition of the C17,20-lyase activity of CYP17 and multi-targeting strategies that affect androgen synthesis and signalling at different points. Some of these strategies—including the drugs orteronel, VT-464 and galeterone—are supported by preclinical data and are being explored in the clinic.

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Figure 1: The production of androgens, their stimulation of prostate cancer cells and hormonal manipulations.
Figure 2: The central role of CYP17 in the biosynthesis route of steroidal hormones.
Figure 3

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Acknowledgements

The authors would like to express their gratitude to Prof. Dr Rolf W. Hartmann for leading them into the field of steroidogenic CYP enzymes.

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Yin, L., Hu, Q. CYP17 inhibitors—abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nat Rev Urol 11, 32–42 (2014). https://doi.org/10.1038/nrurol.2013.274

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