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

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.

Lysophosphatidic acid receptor isoforms expression in prostate cancer cells is differentially regulated by the CYP17A1 inhibitor abiraterone and depends on the androgen receptor

“…Unsurprisingly, LNCaP cells expressing AR were found to be inhibited in the presence of the steroid synthesis doi: 10.18282/amor.v2.i1.83 inhibitor, AA. This observation affirmed the established hypothesis that PC cells exhibit an endogenous de novo synthesis of steroids, which might be targeted by AA's CYP17A1-inhibiting activity, and consequently provided the rationale for the molecular mode of action of the compound [18,19] . Even though Zhang et al could not detect any CYP17A1 expression in LNCaP and PC-3 cells, it is not improbable that AA's anticancer activity may result from the targeting of currently unknown factors in cellular progression [20] .…”

Effect of dutasteride on castration‑resistant prostate cancer

“…These findings are consistent with the reportedly low number of complete clinical responses observed in a trial of neoadjuvant androgen deprivation therapy (10). However, the effectiveness of some next-generation, androgen-modulating drugs (enzalutamide and abiraterone acetate) has been reported (11)(12)(13).…”

“…However, the role of SRD5A inhibitors in the progression of prostate cancer to CRPC has not been well studied (18). The development of CRPC is still dependent on DHT, and some next-generation drugs targeting the androgen signaling pathway were reportedly effective (11)(12)(13). We therefore assessed the effects of dutasteride in patients with CRPC by assessing changes in PSA levels.…”

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

“…Enzalutamide is a second-generation antiandrogen that, unlike first-generation antiandrogens (e.g., flutamide and bicalutamide), prevents the recruitment of the AR to target gene promoters and functions as an antagonist, even in the presence of AR overexpression (11). Abiraterone, on the other hand, belongs to a class of compounds known as CYP17A1 (CYP17) inhibitors that block testicular, adrenal, and intratumoral androgen synthesis (12).…”