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1554665 
Journal Article 
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 
Lieder, F; Reisen, F; Geppert, Tim; Sollberger, G; Beer, HD; Keller, U; Schaefer, M; Detmar, M; Schneider, G; Werner, S 
2012 
Yes 
Journal of Biological Chemistry
ISSN: 0021-9258
EISSN: 1083-351X 
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC 
BETHESDA 
287 
39 
33001-33013 
English 
22851183 
WOS:000309168300063 
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.