Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmac...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2021-11, Vol.64 (21), p.15949-15972
Main Authors: Norton, David, Bonnette, William G, Callahan, James F, Carr, Maria G, Griffiths-Jones, Charlotte M, Heightman, Tom D, Kerns, Jeffrey K, Nie, Hong, Rich, Sharna J, Richardson, Caroline, Rumsey, William, Sanchez, Yolanda, Verdonk, Marcel L, Willems, Henriëtte M. G, Wixted, William E, Woolford, Alison J.-A, Wu, Zining, Davies, Thomas G
Format: Article
Language:English
Subjects:
Animals
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Cell Line
Drug Discovery
Humans
Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors
Kelch-Like ECH-Associated Protein 1 - metabolism
Mice
NF-E2-Related Factor 2 - antagonists & inhibitors
NF-E2-Related Factor 2 - metabolism
Protein Binding
Pyrazoles
Structure-Activity Relationship
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-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133
cites cdi_FETCH-LOGICAL-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133
container_end_page 15972
container_issue 21
container_start_page 15949
container_title Journal of medicinal chemistry
container_volume 64
creator Norton, David
Bonnette, William G
Callahan, James F
Carr, Maria G
Griffiths-Jones, Charlotte M
Heightman, Tom D
Kerns, Jeffrey K
Nie, Hong
Rich, Sharna J
Richardson, Caroline
Rumsey, William
Sanchez, Yolanda
Verdonk, Marcel L
Willems, Henriëtte M. G
Wixted, William E
Woolford, Alison J.-A
Wu, Zining
Davies, Thomas G
description The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein−protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.
doi_str_mv 10.1021/acs.jmedchem.1c01351
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2587753973</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2587753973</sourcerecordid><originalsourceid>FETCH-LOGICAL-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133</originalsourceid><addsrcrecordid>eNp9kc1y0zAURjUMDE0Lb8AwWpaFg_4c291lQtJm2mkzHVh7ZPkaq8hWK8kM7hOw5pX6JjwJSpOw7EqLe74j6X4IfaBkSgmjn6Xy07sOatVCN6WKUJ7SV2hCU0YSkRPxGk0IYSxhM8aP0LH3d4QQThl_i464yEgqUjJBTysnv3fQh-R80DXU-Iv2yv4EN2Lb4M3o5KM1gBfSVfbXaLTCc6VrvO5bXelgnd9ioQV8CUa1idE_AC8XF8nce6u0DNG4cTaA7jE9w9eDMiAdXkkVs3jpxtA6G30M34J5pvcjhk8vl_MNPbu-XbFPB8ff338OtnUfwEVW2_4detNI4-H9_jxB31bLr_ERVzfn68X8KpFc5CGpOVFZqmjBMpbljEoBddyIkAUriqySSjBJiZoVVFAxI3RWpzmRuaxYA6yhnJ-g05333tmHAXwou7gsMEb2YAdfsjTPspQX2RYVO1Q5672Dprx3upNuLCkpt_WVsb7yUF-5ry_GPu5vGKo4-x869BUBsgOe43Zwffzwy85_AheqiQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2587753973</pqid></control><display><type>article</type><title>Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction</title><source>American Chemical Society:Jisc Collections:American Chemical Society Read &amp; Publish Agreement 2022-2024 (Reading list)</source><creator>Norton, David ; Bonnette, William G ; Callahan, James F ; Carr, Maria G ; Griffiths-Jones, Charlotte M ; Heightman, Tom D ; Kerns, Jeffrey K ; Nie, Hong ; Rich, Sharna J ; Richardson, Caroline ; Rumsey, William ; Sanchez, Yolanda ; Verdonk, Marcel L ; Willems, Henriëtte M. G ; Wixted, William E ; Woolford, Alison J.-A ; Wu, Zining ; Davies, Thomas G</creator><creatorcontrib>Norton, David ; Bonnette, William G ; Callahan, James F ; Carr, Maria G ; Griffiths-Jones, Charlotte M ; Heightman, Tom D ; Kerns, Jeffrey K ; Nie, Hong ; Rich, Sharna J ; Richardson, Caroline ; Rumsey, William ; Sanchez, Yolanda ; Verdonk, Marcel L ; Willems, Henriëtte M. G ; Wixted, William E ; Woolford, Alison J.-A ; Wu, Zining ; Davies, Thomas G</creatorcontrib><description>The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein−protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01351</identifier><identifier>PMID: 34705450</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Carboxylic Acids - chemistry ; Carboxylic Acids - pharmacology ; Cell Line ; Drug Discovery ; Humans ; Kelch-Like ECH-Associated Protein 1 - antagonists &amp; inhibitors ; Kelch-Like ECH-Associated Protein 1 - metabolism ; Mice ; NF-E2-Related Factor 2 - antagonists &amp; inhibitors ; NF-E2-Related Factor 2 - metabolism ; Protein Binding ; Pyrazoles ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-11, Vol.64 (21), p.15949-15972</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133</citedby><cites>FETCH-LOGICAL-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133</cites><orcidid>0000-0002-3790-5554 ; 0000-0002-8680-4936 ; 0000-0001-7196-5975 ; 0000-0002-1143-7289 ; 0000-0002-6484-3328 ; 0000-0002-6453-5819</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34705450$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Norton, David</creatorcontrib><creatorcontrib>Bonnette, William G</creatorcontrib><creatorcontrib>Callahan, James F</creatorcontrib><creatorcontrib>Carr, Maria G</creatorcontrib><creatorcontrib>Griffiths-Jones, Charlotte M</creatorcontrib><creatorcontrib>Heightman, Tom D</creatorcontrib><creatorcontrib>Kerns, Jeffrey K</creatorcontrib><creatorcontrib>Nie, Hong</creatorcontrib><creatorcontrib>Rich, Sharna J</creatorcontrib><creatorcontrib>Richardson, Caroline</creatorcontrib><creatorcontrib>Rumsey, William</creatorcontrib><creatorcontrib>Sanchez, Yolanda</creatorcontrib><creatorcontrib>Verdonk, Marcel L</creatorcontrib><creatorcontrib>Willems, Henriëtte M. G</creatorcontrib><creatorcontrib>Wixted, William E</creatorcontrib><creatorcontrib>Woolford, Alison J.-A</creatorcontrib><creatorcontrib>Wu, Zining</creatorcontrib><creatorcontrib>Davies, Thomas G</creatorcontrib><title>Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein−protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.</description><subject>Animals</subject><subject>Carboxylic Acids - chemistry</subject><subject>Carboxylic Acids - pharmacology</subject><subject>Cell Line</subject><subject>Drug Discovery</subject><subject>Humans</subject><subject>Kelch-Like ECH-Associated Protein 1 - antagonists &amp; inhibitors</subject><subject>Kelch-Like ECH-Associated Protein 1 - metabolism</subject><subject>Mice</subject><subject>NF-E2-Related Factor 2 - antagonists &amp; inhibitors</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Protein Binding</subject><subject>Pyrazoles</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kc1y0zAURjUMDE0Lb8AwWpaFg_4c291lQtJm2mkzHVh7ZPkaq8hWK8kM7hOw5pX6JjwJSpOw7EqLe74j6X4IfaBkSgmjn6Xy07sOatVCN6WKUJ7SV2hCU0YSkRPxGk0IYSxhM8aP0LH3d4QQThl_i464yEgqUjJBTysnv3fQh-R80DXU-Iv2yv4EN2Lb4M3o5KM1gBfSVfbXaLTCc6VrvO5bXelgnd9ioQV8CUa1idE_AC8XF8nce6u0DNG4cTaA7jE9w9eDMiAdXkkVs3jpxtA6G30M34J5pvcjhk8vl_MNPbu-XbFPB8ff338OtnUfwEVW2_4detNI4-H9_jxB31bLr_ERVzfn68X8KpFc5CGpOVFZqmjBMpbljEoBddyIkAUriqySSjBJiZoVVFAxI3RWpzmRuaxYA6yhnJ-g05333tmHAXwou7gsMEb2YAdfsjTPspQX2RYVO1Q5672Dprx3upNuLCkpt_WVsb7yUF-5ry_GPu5vGKo4-x869BUBsgOe43Zwffzwy85_AheqiQ</recordid><startdate>20211111</startdate><enddate>20211111</enddate><creator>Norton, David</creator><creator>Bonnette, William G</creator><creator>Callahan, James F</creator><creator>Carr, Maria G</creator><creator>Griffiths-Jones, Charlotte M</creator><creator>Heightman, Tom D</creator><creator>Kerns, Jeffrey K</creator><creator>Nie, Hong</creator><creator>Rich, Sharna J</creator><creator>Richardson, Caroline</creator><creator>Rumsey, William</creator><creator>Sanchez, Yolanda</creator><creator>Verdonk, Marcel L</creator><creator>Willems, Henriëtte M. G</creator><creator>Wixted, William E</creator><creator>Woolford, Alison J.-A</creator><creator>Wu, Zining</creator><creator>Davies, Thomas G</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3790-5554</orcidid><orcidid>https://orcid.org/0000-0002-8680-4936</orcidid><orcidid>https://orcid.org/0000-0001-7196-5975</orcidid><orcidid>https://orcid.org/0000-0002-1143-7289</orcidid><orcidid>https://orcid.org/0000-0002-6484-3328</orcidid><orcidid>https://orcid.org/0000-0002-6453-5819</orcidid></search><sort><creationdate>20211111</creationdate><title>Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction</title><author>Norton, David ; Bonnette, William G ; Callahan, James F ; Carr, Maria G ; Griffiths-Jones, Charlotte M ; Heightman, Tom D ; Kerns, Jeffrey K ; Nie, Hong ; Rich, Sharna J ; Richardson, Caroline ; Rumsey, William ; Sanchez, Yolanda ; Verdonk, Marcel L ; Willems, Henriëtte M. G ; Wixted, William E ; Woolford, Alison J.-A ; Wu, Zining ; Davies, Thomas G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Carboxylic Acids - chemistry</topic><topic>Carboxylic Acids - pharmacology</topic><topic>Cell Line</topic><topic>Drug Discovery</topic><topic>Humans</topic><topic>Kelch-Like ECH-Associated Protein 1 - antagonists &amp; inhibitors</topic><topic>Kelch-Like ECH-Associated Protein 1 - metabolism</topic><topic>Mice</topic><topic>NF-E2-Related Factor 2 - antagonists &amp; inhibitors</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Protein Binding</topic><topic>Pyrazoles</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Norton, David</creatorcontrib><creatorcontrib>Bonnette, William G</creatorcontrib><creatorcontrib>Callahan, James F</creatorcontrib><creatorcontrib>Carr, Maria G</creatorcontrib><creatorcontrib>Griffiths-Jones, Charlotte M</creatorcontrib><creatorcontrib>Heightman, Tom D</creatorcontrib><creatorcontrib>Kerns, Jeffrey K</creatorcontrib><creatorcontrib>Nie, Hong</creatorcontrib><creatorcontrib>Rich, Sharna J</creatorcontrib><creatorcontrib>Richardson, Caroline</creatorcontrib><creatorcontrib>Rumsey, William</creatorcontrib><creatorcontrib>Sanchez, Yolanda</creatorcontrib><creatorcontrib>Verdonk, Marcel L</creatorcontrib><creatorcontrib>Willems, Henriëtte M. G</creatorcontrib><creatorcontrib>Wixted, William E</creatorcontrib><creatorcontrib>Woolford, Alison J.-A</creatorcontrib><creatorcontrib>Wu, Zining</creatorcontrib><creatorcontrib>Davies, Thomas G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Norton, David</au><au>Bonnette, William G</au><au>Callahan, James F</au><au>Carr, Maria G</au><au>Griffiths-Jones, Charlotte M</au><au>Heightman, Tom D</au><au>Kerns, Jeffrey K</au><au>Nie, Hong</au><au>Rich, Sharna J</au><au>Richardson, Caroline</au><au>Rumsey, William</au><au>Sanchez, Yolanda</au><au>Verdonk, Marcel L</au><au>Willems, Henriëtte M. G</au><au>Wixted, William E</au><au>Woolford, Alison J.-A</au><au>Wu, Zining</au><au>Davies, Thomas G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2021-11-11</date><risdate>2021</risdate><volume>64</volume><issue>21</issue><spage>15949</spage><epage>15972</epage><pages>15949-15972</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein−protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34705450</pmid><doi>10.1021/acs.jmedchem.1c01351</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-3790-5554</orcidid><orcidid>https://orcid.org/0000-0002-8680-4936</orcidid><orcidid>https://orcid.org/0000-0001-7196-5975</orcidid><orcidid>https://orcid.org/0000-0002-1143-7289</orcidid><orcidid>https://orcid.org/0000-0002-6484-3328</orcidid><orcidid>https://orcid.org/0000-0002-6453-5819</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 0022-2623
ispartof Journal of medicinal chemistry, 2021-11, Vol.64 (21), p.15949-15972
issn 0022-2623
1520-4804
language eng
recordid cdi_proquest_miscellaneous_2587753973
source American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
subjects Animals
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Cell Line
Drug Discovery
Humans
Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors
Kelch-Like ECH-Associated Protein 1 - metabolism
Mice
NF-E2-Related Factor 2 - antagonists & inhibitors
NF-E2-Related Factor 2 - metabolism
Protein Binding
Pyrazoles
Structure-Activity Relationship
title Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T02%3A51%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fragment-Guided%20Discovery%20of%20Pyrazole%20Carboxylic%20Acid%20Inhibitors%20of%20the%20Kelch-like%20ECH-Associated%20Protein%201:%20Nuclear%20Factor%20Erythroid%202%20Related%20Factor%202%20(KEAP1:NRF2)%20Protein%E2%88%92Protein%20Interaction&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Norton,%20David&rft.date=2021-11-11&rft.volume=64&rft.issue=21&rft.spage=15949&rft.epage=15972&rft.pages=15949-15972&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.1c01351&rft_dat=%3Cproquest_cross%3E2587753973%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-a348t-d30c75c192727821a4ed0034a92997bac42a10c6914146016d580a8ab2fe2f133%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2587753973&rft_id=info:pmid/34705450&rfr_iscdi=true