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

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 m...

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Bibliographic Details
Published in:Biochimica et biophysica acta. Proteins and proteomics 2020-07, Vol.1868 (7), p.140405, Article 140405
Main Authors: Madden, Sarah K., Itzhaki, Laura S.
Format: Article
Language:English
Subjects:
Covalent inhibitors
Cul3
E3 ubiquitin ligase
Keap1
Nrf2
PROTACs
Protein-protein interactions
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Summary: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.
ISSN:1570-9639
1878-1454
DOI:10.1016/j.bbapap.2020.140405