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

Bioorg Med Chem. 2013 Jul 15;21(14):4011-9. doi: 10.1016/j.bmc.2013.04.019. Epub 2013 Apr 19.

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.

MeSH terms

  • Carrier Proteins
  • Crystallography, X-Ray
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / chemistry
  • NF-E2-Related Factor 2 / metabolism*
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Small Molecule Libraries / pharmacology*
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • KLHDC1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Small Molecule Libraries