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...

Full description

Saved in:
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3
cites cdi_FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3
container_end_page
container_issue 7
container_start_page 140405
container_title Biochimica et biophysica acta. Proteins and proteomics
container_volume 1868
creator Madden, Sarah K.
Itzhaki, Laura S.
description 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.
doi_str_mv 10.1016/j.bbapap.2020.140405
format article
fullrecord <record><control><sourceid>elsevier_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1016_j_bbapap_2020_140405</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1570963920300467</els_id><sourcerecordid>S1570963920300467</sourcerecordid><originalsourceid>FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3</originalsourceid><addsrcrecordid>eNp9kM9KAzEQh4MoVqtvIJIX2DrJJpvdiyDFf1j0oJ48hCSbbVO63SXJFvr2pqx69DTD8P1mhg-hKwIzAqS4Wc-0Vr3qZxRoGjFgwI_QGSlFmRHG2XHquYCsKvJqgs5DWEMCheCnaJJTQgGIOENf79EPJg5ebbDa1ri1ZqW2LkRnsNsGt1zFkJrY4biy-MWqnmSvvqE47EO0LVYBK-y7IVqcmNoPS1y7YLqd9fsLdNKoTbCXP3WKPh_uP-ZP2eLt8Xl-t8hMXtCY1ZQZoYlWOTcArGqEYpoANQrK0lDKC-CmFBUrqKaN1pYbw1hDQedCFY3Np4iNe43vQvC2kb13rfJ7SUAeXMm1HF3Jgys5ukqx6zHWD7q19V_oV04CbkfApud3znoZjLNbY2vnrYmy7tz_F74B_8x8fw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery</title><source>ScienceDirect Freedom Collection 2022-2024</source><creator>Madden, Sarah K. ; Itzhaki, Laura S.</creator><creatorcontrib>Madden, Sarah K. ; Itzhaki, Laura S.</creatorcontrib><description>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.</description><identifier>ISSN: 1570-9639</identifier><identifier>EISSN: 1878-1454</identifier><identifier>DOI: 10.1016/j.bbapap.2020.140405</identifier><identifier>PMID: 32120017</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Covalent inhibitors ; Cul3 ; E3 ubiquitin ligase ; Keap1 ; Nrf2 ; PROTACs ; Protein-protein interactions</subject><ispartof>Biochimica et biophysica acta. Proteins and proteomics, 2020-07, Vol.1868 (7), p.140405, Article 140405</ispartof><rights>2020</rights><rights>Copyright © 2020. Published by Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3</citedby><cites>FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32120017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Madden, Sarah K.</creatorcontrib><creatorcontrib>Itzhaki, Laura S.</creatorcontrib><title>Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery</title><title>Biochimica et biophysica acta. Proteins and proteomics</title><addtitle>Biochim Biophys Acta Proteins Proteom</addtitle><description>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.</description><subject>Covalent inhibitors</subject><subject>Cul3</subject><subject>E3 ubiquitin ligase</subject><subject>Keap1</subject><subject>Nrf2</subject><subject>PROTACs</subject><subject>Protein-protein interactions</subject><issn>1570-9639</issn><issn>1878-1454</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kM9KAzEQh4MoVqtvIJIX2DrJJpvdiyDFf1j0oJ48hCSbbVO63SXJFvr2pqx69DTD8P1mhg-hKwIzAqS4Wc-0Vr3qZxRoGjFgwI_QGSlFmRHG2XHquYCsKvJqgs5DWEMCheCnaJJTQgGIOENf79EPJg5ebbDa1ri1ZqW2LkRnsNsGt1zFkJrY4biy-MWqnmSvvqE47EO0LVYBK-y7IVqcmNoPS1y7YLqd9fsLdNKoTbCXP3WKPh_uP-ZP2eLt8Xl-t8hMXtCY1ZQZoYlWOTcArGqEYpoANQrK0lDKC-CmFBUrqKaN1pYbw1hDQedCFY3Np4iNe43vQvC2kb13rfJ7SUAeXMm1HF3Jgys5ukqx6zHWD7q19V_oV04CbkfApud3znoZjLNbY2vnrYmy7tz_F74B_8x8fw</recordid><startdate>202007</startdate><enddate>202007</enddate><creator>Madden, Sarah K.</creator><creator>Itzhaki, Laura S.</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>202007</creationdate><title>Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery</title><author>Madden, Sarah K. ; Itzhaki, Laura S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Covalent inhibitors</topic><topic>Cul3</topic><topic>E3 ubiquitin ligase</topic><topic>Keap1</topic><topic>Nrf2</topic><topic>PROTACs</topic><topic>Protein-protein interactions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Madden, Sarah K.</creatorcontrib><creatorcontrib>Itzhaki, Laura S.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Biochimica et biophysica acta. Proteins and proteomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Madden, Sarah K.</au><au>Itzhaki, Laura S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery</atitle><jtitle>Biochimica et biophysica acta. Proteins and proteomics</jtitle><addtitle>Biochim Biophys Acta Proteins Proteom</addtitle><date>2020-07</date><risdate>2020</risdate><volume>1868</volume><issue>7</issue><spage>140405</spage><pages>140405-</pages><artnum>140405</artnum><issn>1570-9639</issn><eissn>1878-1454</eissn><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.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>32120017</pmid><doi>10.1016/j.bbapap.2020.140405</doi></addata></record>
fulltext fulltext
identifier ISSN: 1570-9639
ispartof Biochimica et biophysica acta. Proteins and proteomics, 2020-07, Vol.1868 (7), p.140405, Article 140405
issn 1570-9639
1878-1454
language eng
recordid cdi_crossref_primary_10_1016_j_bbapap_2020_140405
source ScienceDirect Freedom Collection 2022-2024
subjects Covalent inhibitors
Cul3
E3 ubiquitin ligase
Keap1
Nrf2
PROTACs
Protein-protein interactions
title Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T16%3A59%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-elsevier_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structural%20and%20mechanistic%20insights%20into%20the%20Keap1-Nrf2%20system%20as%20a%20route%20to%20drug%20discovery&rft.jtitle=Biochimica%20et%20biophysica%20acta.%20Proteins%20and%20proteomics&rft.au=Madden,%20Sarah%20K.&rft.date=2020-07&rft.volume=1868&rft.issue=7&rft.spage=140405&rft.pages=140405-&rft.artnum=140405&rft.issn=1570-9639&rft.eissn=1878-1454&rft_id=info:doi/10.1016/j.bbapap.2020.140405&rft_dat=%3Celsevier_cross%3ES1570963920300467%3C/elsevier_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c362t-d24c7b1ba35c0049f7a4b102ca088c225605c879462b2fbbe5cc44f20b37a6fe3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/32120017&rfr_iscdi=true