Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery

Sarah K Madden, Laura S Itzhaki

Research output: Contribution to journalReview articlepeer-review

13 Citations (Scopus)

Abstract

The proteins Keap1 and Nrf2 together act as a cytoprotective mechanism that enables cells to overcome electrophilic and oxidative stress. Research has shown that manipulating this system by modulating the Keap1-Nrf2 interaction either through inhibition at the binding interface or via the covalent modification of Keap1 could provide a powerful therapeutic strategy for a range of diseases. However, despite intensive investigation of the system and significant progress in the development of inhibitory small molecules, there is still much to learn about the pathways associated with the Keap1-Nrf2 system and the structural details underpinning its mechanism of action. In this review, we discuss how a deeper understanding could prove revolutionary in the development of new inhibitors and activators as well as guiding how to best harness Keap1 for targeted protein degradation.

Original languageEnglish
Article number140405
JournalBiochimica Et Biophysica Acta-Proteins and Proteomics
Volume1868
Issue number7
Early online date28 Feb 2020
DOIs
Publication statusPublished - 1 Jul 2020

Keywords

  • Covalent inhibitors
  • Cul3
  • E3 ubiquitin ligase
  • Keap1
  • Nrf2
  • PROTACs
  • Protein-protein interactions

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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