Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism
| Autor: | Matvey E. Lukashev, Victor Hong, Hernan Cuervo, Ping Jin, Douglas Marcotte, Alexey Lugovskoy, Valérie Vivat, C Hession, Deping Wang, Joachim Kraemer, Jean-Christophe Hus, Chris Bergeron, Dominique Roecklin, Weike Zeng, Malgorzata M. Vecchi, Dirk Winkler, Istvan J. Enyedy, Cédric Atmanene, Laura Silvian, Andres McKenzie, Jianhua Chao |
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| Rok vydání: | 2013 |
| Předmět: |
Spectrometry
Mass Electrospray Ionization NF-E2-Related Factor 2 Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry Small Molecule Libraries Structure-Activity Relationship Transcription (biology) Drug Discovery Luciferase Molecular Biology Transcription factor Reporter gene Kelch-Like ECH-Associated Protein 1 Chemistry Organic Chemistry Intracellular Signaling Peptides and Proteins KEAP1 Small molecule Protein Structure Tertiary Biophysics Thermodynamics Molecular Medicine Carrier Proteins Protein Binding Cysteine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:4011-4019 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2013.04.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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