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

Silvia Bonomo,Lars Olsen,Cecilie H Hansen,Bjarne Styrishave,Flemming Steen Jørgensen,Emily E Scott,Elyse M Petrunak

doi:10.1038/srep29468

Silvia Bonomo, Lars Olsen + Show 5 more

Open Access

https://doi.org/10.1038/srep29468

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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 non-steroidal 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 IC50 values in the nanomolar range, without affinity for the major drug-metabolizing CYP2D6 and CYP3A4 enzymes and CYP21A2, with the latter result confirmed in human H295R cells.

Highlights

Prostate cancer (PCa) is the second most common type of cancer in men and the fifth leading cause of death worldwide[1]
The binding energy was calculated for the interaction of the most common sp2-hybridized N-containing rings with the haem using the density functional theory (DFT) method according to the scheme shown in Fig. 3 and were in agreement with data previously published[21]
Cancer cells quickly acquire the ability to produce male hormones autonomously, resulting in resistance to androgen deprivation therapy (ADT) that is the hallmark of castration-resistant prostate cancer (CRPC)

Summary

Introduction

Prostate cancer (PCa) is the second most common type of cancer in men and the fifth leading cause of death worldwide[1]. Despite the increasing number of cytochrome P450 X-ray structures, the presence of a haem cofactor makes these enzymes a challenging type of system from the computational chemistry point of view. This is because many inhibitors coordinate directly to the haem iron, e.g. with sp2-hybridized nitrogen atoms. Force field-based docking algorithms fail to properly describe this type of semi-covalent bond formation[15,16] To overcome this problem, density functional theory (DFT) calculations were used to describe the nitrogen-iron interaction[17] in combination with a haem-tailored structure-based virtual screening to suggest novel non-steroidal CYP17A1 inhibitors

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Conclusion