Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 103, Issue -, Pages 252-268Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.08.049
Keywords
Nrf2; Keap1; Protein-protein interaction; Transcription factor; Cul3; Keap1/Nrf2 interaction
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Funding
- University of Illinois at Chicago College of Pharmacy
- University of Illinois Cancer Center
- National Institutes of Health [HL66109, ES11863]
- Walther Cancer Foundation
- [P30 CA023168]
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Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a K-d of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane. (C) 2015 Elsevier Masson SAS. All rights reserved.
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