title: 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 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.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonomo
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Cecilie H
authors.initials: CH
authors.lastname: Hansen
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS, 66045 USA.
authors.forename: Elyse M
authors.initials: EM
authors.lastname: Petrunak
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS, 66045 USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Scott
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Styrishave
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark.
authors.forename: Flemming Steen
authors.initials: FS
authors.lastname: Jørgensen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
mesh_terms: D000736:Androstenes / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry; D062105:Molecular Docking Simulation; D009584:Nitrogen / Q000737:chemistry; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy*; D011485:Protein Binding; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D013256:Steroids
chemical_list: D000736:Androstenes; D008024:Ligands; D013256:Steroids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; D009584:Nitrogen