Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Abstract

Cytochrome P450 17A1 (CYP17A1) is an important target in the treatment of prostate cancer because it produces androgens required for tumour growth. The FDA has approved only one CYP17A1 inhibitor, abiraterone, which contains a steroidal scaffold similar to the endogenous CYP17A1 substrates. Abiraterone is structurally similar to the substrates of other cytochrome P450 enzymes involved in steroidogenesis, and interference can pose a liability in terms of side effects. Using nonsteroidal scaffolds is expected to enable the design of compounds that interact more selectively with CYP17A1. Therefore, we combined a structure-based virtual screening approach with density functional theory (DFT) calculations to suggest non-steroidal compounds selective for CYP17A1. In vitro assays demonstrated that two such compounds selectively inhibited CYP17A1 17α-hydroxylase and 17,20-lyase activities with IC 50 values in the nanomolar range, without affinity for the major drugmetabolizing CYP2D6 and CYP3A4 enzymes and CYP21A2, with the latter result confirmed in human H295R cells.Prostate cancer (PCa) is the second most common type of cancer in men and the fifth leading cause of death worldwide 1 . Several treatments have been developed against PCa, but drug resistance occurs rapidly, leading to a disease state known as castration-resistant prostate cancer (CRPC) 2,3 . In CRPC, androgens produced by the tumour and/or the adrenal gland drive disease progression. Thus, reduction or suppression of hormone levels in the cancer cells remains a key point in advanced stages of the disease.Cytochrome P450 17A1 (CYP17A1) is a monooxygenase involved in the synthesis of steroidal hormones. CYP17A1 converts pregnenolone to dehydroepiandrosterone and progesterone to androstenedione by two subsequent reactions, the 17α -hydroxylase and 17,20-lyase reactions (cf. Fig. 1). The hydroxylase reaction generates intermediates in the biosynthesis of glucocorticoids, while both hydroxylase and lyase reactions are required for biosynthesis of androgens and oestrogens 4 . CYP17A1 is therefore a pivotal target in the treatment of hormone-dependent tumours such as prostate cancer [5][6][7] .Several CYP17A1 inhibitors have been developed over the years, but only abiraterone (cf. Fig. 2) has been approved by the FDA for treating CRPC. Abiraterone consists of a steroidal scaffold with a pyridin-3-yl moiety in position 17 that inhibits CYP17A1 through coordination to the haem iron 8 . Oxygen binding to the haem iron is necessary for all CYP17A1 catalysis, so abiraterone binding is inhibitory. Together, the steroidal scaffold and the aromatic nitrogen-containing ring give abiraterone a promiscuous profile with affinity toward steroid receptors and other CYP enzymes, which likely contribute to the undesirable side effects observed in patients receiving abiraterone treatment 9 . Combinatorial synthesis programmes have been started by pharmaceutical companies to identify non-steroidal inhibitors and two such compounds, orteronel 10 and VT-464 11 , have been evaluate...

Importance of Azo‐Hydrazo Tautomerization in the Oxidative Degradation of Procarbazine by Cytochrome P450: Computational Insights

“…The obtained zero‐point corrections (ZPE) were considered in all of the data analysis. The B3LYP/LACVP* method indicated very reliable results for mechanistic studies of cytochrome P450 compounds . Compound I can exist in both doublet and quartet spin states.…”

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…These compounds do not bind selected drug-metabolising cytochrome P450 enzymes or the steroidogenic CYP21A2, suggesting a reduced risk for undesirable side effects, especially on the corticosteroid production, consistent with data observed in vitro. Taken together, these data recommend compounds 6 and 7 as promising tools for the continued development of new drugs against PCa [42] .…”

“…Aggarwal et al [98] studied similar steroidal molecules (structures [42][43][44] able to inhibit the type II enzyme in the same range of concentration as finasteride.…”

“…Subsequently, the combination of a structure-based virtual screening approach with density functional theory calculations was used to suggest newnon- steroidal compounds selective for CYP17A1 [42] . This second study afforded the discovery of compound 7.…”

Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer

“…3 Treatment typically includes the androgen receptor (AR) antagonist enzalutamide (Xtandi ® ) 4,5 that directly antagonizes the AR or abiraterone acetate (Zytiga ® ), a molecule that blocks the synthesis of androgens. 6,7 Despite this chemical castration approach, recurrence is common and within 2–3 years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies such as enzalutamide and abiraterone. 3 At this stage of the disease, advanced castration resistant prostate cancer (CRPC), the AR in these tumors has adapted to the stress of treatment resulting in alternative splicing, AR mutation, or over expression of the AR to overcome treatment regimes.…”