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      Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.

      Bioorganic & Medicinal Chemistry

      Carrier Proteins, Crystallography, X-Ray, Intracellular Signaling Peptides and Proteins, antagonists & inhibitors, chemistry, metabolism, NF-E2-Related Factor 2, Protein Binding, drug effects, Protein Structure, Tertiary, Small Molecule Libraries, pharmacology, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Thermodynamics

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          Abstract

          Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification. Copyright © 2013 Elsevier Ltd. All rights reserved.

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          Journal
          23647822
          10.1016/j.bmc.2013.04.019

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