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Updated Research and Applications of Small Molecule Inhibitors of Keap1-Nrf2 Protein-Protein Interaction: a Review

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The Keap1-Nrf2-ARE pathway is one of the most important regulators of cytoprotective responses to oxidative and/or electrophilic stresses, which is believed to play a critical role in the development of many diseases, such as cancer, Alzheimer’s, Parkinson’s, and inflammatory bowel disease. Recent research indicates that the modulation of ARE activation via direct inhibition of the Keap1-Nrf2protein-protein interaction has many advantages, particularly the low cytotoxicity, over indirect covalent modulators of Keap1 protein for the discovery of novel small molecule modulators of this pathway. However, most known inducers (e.g., triterpenoids, isothiocyanates and sulfoxythiocarbamates) that activate the ARE system through electrophilic attacks on the cysteine sulfhydryl group of Keap1 also disrupt theKeap1-Nrf2 interaction. The understanding of co-crystal complex of the Keap1-Nrf2 interactionthus provides a structural basis for the rational design of highly potent direct inhibitors. This review summarizes the recent advances in the medicinal chemistry of small-molecule inhibitors in the areas of drug design, structure-activity relationships, and biological and biochemical properties. The peptides designed from DLG and ETGE motifs of Nrf2 protein that binds to Keap1 Kelch domain with promising binding affinities are highlighted. This review also includes recently reported non-peptide inhibitors with moderate inhibition by high-throughput screening. It is clear that further research is required for the discovery of more potent inhibitors.
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Keywords: Inhibitor; Keap1; Nrf2; peptide; protein-protein interaction; review; small molecule

Document Type: Research Article

Publication date: May 1, 2014

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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