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

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (39), p.33001-33013
• Main Authors: Lieder, Franziska, Reisen, Felix, Geppert, Tim, Sollberger, Gabriel, Beer, Hans-Dietmar, auf dem Keller, Ulrich, Schäfer, Matthias, Detmar, Michael, Schneider, Gisbert, Werner, Sabine
• Format: Article
• Language: English
• Subjects: Animals; Benzamides - pharmacology; Cell Death - drug effects; Cell Death - genetics; Cell Death - radiation effects; Cell Line, Transformed; Chemical Biology; Chemical Library; Chemoprevention; Cytoprotection - drug effects; Cytoprotection - genetics; Cytoprotection - radiation effects; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Expression Regulation - radiation effects; Gene Regulation; Humans; Keratinocytes - metabolism; Keratinocytes - pathology; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress; Skin - injuries; Skin - metabolism; Skin - pathology; Transcription Factors; Ultraviolet Rays - adverse effects; Virtual Screening
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.383430

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. Background: The Nrf2 transcription factor is a master regulator of cellular antioxidant defense systems. Results: We identified novel Nrf2 activators in keratinocytes with low toxicity and strong UV-protective potential. Conclusion: Chemical library screening combined with virtual screening is a potent strategy to identify optimized Nrf2 activators. Significance: Our new Nrf2 activators are potential lead compounds for the development of drugs for skin protection under stress conditions.