Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 14, Pages 4011-4019Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.04.019
Keywords
Nrf2; Keap1; Protein-protein interaction inhibitor; Oxidative stress; ESI-MS; X-ray crystallography
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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. (C) 2013 Elsevier Ltd. All rights reserved.
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