Identification of UV-protective activators of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) by combining a chemical library screen with computer-based virtual screening

Franziska Lieder, Felix Reisen, Tim Geppert, Gabriel Sollberger, Hans Dietmar Beer, Ulrich Auf Dem Keller, Matthias Schäfer, Michael Detmar, Gisbert Schneider, Sabine Werner (Lead / Corresponding author)

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant defense systems, and activation of this transcription factor is a promising strategy for protection of skin and other organs from environmental insults. To identify efficient Nrf2 activators in keratinocytes, we combined a chemical library screen with computer-based virtual screening. Among 14 novel Nrf2 activators, the most potent compound, a nitrophenyl derivative of 2-chloro-5-nitro-N-phenyl-benzamide, was characterized with regard to its molecular mechanism of action. This compound induced the expression of cytoprotective genes in keratinocytes isolated from wild-type but not from Nrf2-deficient mice. Most importantly, it showed low toxicity and protected primary human keratinocytes from UVB-induced cell death. Therefore, it represents a potential lead compound for the development of drugs for skin protection under stress conditions. Our study demonstrates that chemical library screening combined with advanced computational similarity searching is a powerful strategy for identification of bioactive compounds, and it points toward an innovative therapeutic approach against UVB-induced skin damage.

Original languageEnglish
Pages (from-to)33001-33013
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number39
Early online date31 Jul 2012
DOIs
Publication statusPublished - 21 Sep 2012

Keywords

  • Chemical Biology
  • Chemoprevention
  • Nrf2
  • Oxidative Stress
  • Transcription Factors
  • UV
  • Chemical Library
  • Virtual Screening

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