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

Biochim Biophys Acta Proteins Proteom. 2020 Jul;1868(7):140405. doi: 10.1016/j.bbapap.2020.140405. Epub 2020 Feb 28.

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.

Keywords: Covalent inhibitors; Cul3; E3 ubiquitin ligase; Keap1; Nrf2; PROTACs; Protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Cullin Proteins / metabolism
  • Drug Discovery*
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / chemistry*
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Models, Molecular
  • NF-E2-Related Factor 2 / chemistry*
  • NF-E2-Related Factor 2 / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • CUL3 protein, human
  • Cullin Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Ubiquitin-Protein Ligases