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

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

Research output: Contribution to journalJournal articleResearchpeer-review

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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 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 17 alpha-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.
Original languageEnglish
Article number29468
JournalScientific Reports
Volume6
Number of pages26
ISSN2045-2322
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Journal Article
  • Multidisciplinary
  • MULTIDISCIPLINARY
  • STEROID-HORMONES
  • AROMATASE INHIBITORS
  • DRUG DEVELOPMENT
  • DENSITY
  • DISCOVERY
  • LIGANDS
  • ENZYMES
  • DESIGN
  • CYP17
  • METABOLISM
  • Prostatic Neoplasms
  • Biochemistry studies - Proteins, peptides and amino acids
  • Enzymes - General and comparative studies: coenzymes
  • Pathology - Therapy
  • Urinary system - Pathology
  • Reproductive system - Physiology and biochemistry
  • Reproductive system - Pathology
  • Pharmacology - General
  • Neoplasms - Pathology, clinical aspects and systemic effects
  • Neoplasms - Therapeutic agents and therapy
  • cytochrome P450 3A4
  • cytochrome P450 2D6
  • abiraterone
  • steroidogenesis
  • enzyme activity

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