Covalent Inhibitors of KEAP1 with Exquisite Selectivity
The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting wi...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2024-12, Vol.67 (23), p.21208-21222 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 21222 |
|---|---|
| container_issue | 23 |
| container_start_page | 21208 |
| container_title | Journal of medicinal chemistry |
| container_volume | 67 |
| creator | Fejes, Imre Markacz, Piroska Tatai, Janos Rudas, Monika Dunkel, Petra Gyuris, Mario Nyerges, Miklos Provost, Nicolas Duvivier, Valérie Delerive, Philippe Martiny, Virginie Bristiel, Alexandra Vidal, Brice Richardson, William Rothweiler, Elisabeth M. Tranberg-Jensen, Jeppe Manning, Charlotte E. Sweeney, Melissa N. Chalk, Rod Huber, Kilian V. M. Bullock, Alex N. Herner, Andras Seedorf, Klaus Vinson, Cedric Weber, Csaba Kotschy, Andras |
| description | The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography. |
| doi_str_mv | 10.1021/acs.jmedchem.4c02019 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11647895</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3131851050</sourcerecordid><originalsourceid>FETCH-LOGICAL-a283t-6079019c6d20316aad78fd7481dc236b2136cf36b841a2c19e83ddfcc1d24f03</originalsourceid><addsrcrecordid>eNp9kE1PwyAYx4nRuDn9Bsb06KWTB_p6MmaZurhEE3cnDKhlactW6HTfXuZeohdPkPB_44fQNeAhYAJ3XNjholZSlKoeRgITDPkJ6kNMcBhlODpFfYwJCUlCaA9dWLvAGFMg9Bz1aB6nXk_6KB2ZNa9U44JJU-q5dqa1gSmCl_HDGwSf2pXB-GvVaaudCt5VpYTTa-02l-is4JVVV_tzgGaP49noOZy-Pk1GD9OQk4y6MMFp7neJRBLfnXAu06yQaZSBFIQmcwI0EYW_ZBFwIiBXGZWyEAIkiQpMB-h-F7vs5tu_-qEtr9iy1TVvN8xwzf6-NLpkH2bNAJIozfLYJ9zuE1qz6pR1rNZWqKrijTKdZRQoZDHgeFsW7aSiNda2qjj2AGZb5swzZwfmbM_c225-bzyaDpC9AO8EP3bTtY0n9n_mN-ZVkMA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3131851050</pqid></control><display><type>article</type><title>Covalent Inhibitors of KEAP1 with Exquisite Selectivity</title><source>ACS Publications</source><source>MEDLINE</source><creator>Fejes, Imre ; Markacz, Piroska ; Tatai, Janos ; Rudas, Monika ; Dunkel, Petra ; Gyuris, Mario ; Nyerges, Miklos ; Provost, Nicolas ; Duvivier, Valérie ; Delerive, Philippe ; Martiny, Virginie ; Bristiel, Alexandra ; Vidal, Brice ; Richardson, William ; Rothweiler, Elisabeth M. ; Tranberg-Jensen, Jeppe ; Manning, Charlotte E. ; Sweeney, Melissa N. ; Chalk, Rod ; Huber, Kilian V. M. ; Bullock, Alex N. ; Herner, Andras ; Seedorf, Klaus ; Vinson, Cedric ; Weber, Csaba ; Kotschy, Andras</creator><creatorcontrib>Fejes, Imre ; Markacz, Piroska ; Tatai, Janos ; Rudas, Monika ; Dunkel, Petra ; Gyuris, Mario ; Nyerges, Miklos ; Provost, Nicolas ; Duvivier, Valérie ; Delerive, Philippe ; Martiny, Virginie ; Bristiel, Alexandra ; Vidal, Brice ; Richardson, William ; Rothweiler, Elisabeth M. ; Tranberg-Jensen, Jeppe ; Manning, Charlotte E. ; Sweeney, Melissa N. ; Chalk, Rod ; Huber, Kilian V. M. ; Bullock, Alex N. ; Herner, Andras ; Seedorf, Klaus ; Vinson, Cedric ; Weber, Csaba ; Kotschy, Andras</creatorcontrib><description>The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c02019</identifier><identifier>PMID: 39572012</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Crystallography, X-Ray ; Humans ; Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors ; Kelch-Like ECH-Associated Protein 1 - metabolism ; Mice ; Models, Molecular ; NF-E2-Related Factor 2 - antagonists & inhibitors ; NF-E2-Related Factor 2 - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2024-12, Vol.67 (23), p.21208-21222</ispartof><rights>2024 The Authors. Published by American Chemical Society</rights><rights>2024 The Authors. Published by American Chemical Society 2024 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a283t-6079019c6d20316aad78fd7481dc236b2136cf36b841a2c19e83ddfcc1d24f03</cites><orcidid>0000-0002-6866-3957 ; 0000-0001-5445-8357 ; 0000-0001-8067-4766 ; 0000-0002-1103-5300 ; 0000-0002-7675-3864 ; 0000-0001-6757-0436</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.4c02019$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02019$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39572012$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fejes, Imre</creatorcontrib><creatorcontrib>Markacz, Piroska</creatorcontrib><creatorcontrib>Tatai, Janos</creatorcontrib><creatorcontrib>Rudas, Monika</creatorcontrib><creatorcontrib>Dunkel, Petra</creatorcontrib><creatorcontrib>Gyuris, Mario</creatorcontrib><creatorcontrib>Nyerges, Miklos</creatorcontrib><creatorcontrib>Provost, Nicolas</creatorcontrib><creatorcontrib>Duvivier, Valérie</creatorcontrib><creatorcontrib>Delerive, Philippe</creatorcontrib><creatorcontrib>Martiny, Virginie</creatorcontrib><creatorcontrib>Bristiel, Alexandra</creatorcontrib><creatorcontrib>Vidal, Brice</creatorcontrib><creatorcontrib>Richardson, William</creatorcontrib><creatorcontrib>Rothweiler, Elisabeth M.</creatorcontrib><creatorcontrib>Tranberg-Jensen, Jeppe</creatorcontrib><creatorcontrib>Manning, Charlotte E.</creatorcontrib><creatorcontrib>Sweeney, Melissa N.</creatorcontrib><creatorcontrib>Chalk, Rod</creatorcontrib><creatorcontrib>Huber, Kilian V. M.</creatorcontrib><creatorcontrib>Bullock, Alex N.</creatorcontrib><creatorcontrib>Herner, Andras</creatorcontrib><creatorcontrib>Seedorf, Klaus</creatorcontrib><creatorcontrib>Vinson, Cedric</creatorcontrib><creatorcontrib>Weber, Csaba</creatorcontrib><creatorcontrib>Kotschy, Andras</creatorcontrib><title>Covalent Inhibitors of KEAP1 with Exquisite Selectivity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.</description><subject>Animals</subject><subject>Crystallography, X-Ray</subject><subject>Humans</subject><subject>Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors</subject><subject>Kelch-Like ECH-Associated Protein 1 - metabolism</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>NF-E2-Related Factor 2 - antagonists & inhibitors</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1PwyAYx4nRuDn9Bsb06KWTB_p6MmaZurhEE3cnDKhlactW6HTfXuZeohdPkPB_44fQNeAhYAJ3XNjholZSlKoeRgITDPkJ6kNMcBhlODpFfYwJCUlCaA9dWLvAGFMg9Bz1aB6nXk_6KB2ZNa9U44JJU-q5dqa1gSmCl_HDGwSf2pXB-GvVaaudCt5VpYTTa-02l-is4JVVV_tzgGaP49noOZy-Pk1GD9OQk4y6MMFp7neJRBLfnXAu06yQaZSBFIQmcwI0EYW_ZBFwIiBXGZWyEAIkiQpMB-h-F7vs5tu_-qEtr9iy1TVvN8xwzf6-NLpkH2bNAJIozfLYJ9zuE1qz6pR1rNZWqKrijTKdZRQoZDHgeFsW7aSiNda2qjj2AGZb5swzZwfmbM_c225-bzyaDpC9AO8EP3bTtY0n9n_mN-ZVkMA</recordid><startdate>20241212</startdate><enddate>20241212</enddate><creator>Fejes, Imre</creator><creator>Markacz, Piroska</creator><creator>Tatai, Janos</creator><creator>Rudas, Monika</creator><creator>Dunkel, Petra</creator><creator>Gyuris, Mario</creator><creator>Nyerges, Miklos</creator><creator>Provost, Nicolas</creator><creator>Duvivier, Valérie</creator><creator>Delerive, Philippe</creator><creator>Martiny, Virginie</creator><creator>Bristiel, Alexandra</creator><creator>Vidal, Brice</creator><creator>Richardson, William</creator><creator>Rothweiler, Elisabeth M.</creator><creator>Tranberg-Jensen, Jeppe</creator><creator>Manning, Charlotte E.</creator><creator>Sweeney, Melissa N.</creator><creator>Chalk, Rod</creator><creator>Huber, Kilian V. M.</creator><creator>Bullock, Alex N.</creator><creator>Herner, Andras</creator><creator>Seedorf, Klaus</creator><creator>Vinson, Cedric</creator><creator>Weber, Csaba</creator><creator>Kotschy, Andras</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6866-3957</orcidid><orcidid>https://orcid.org/0000-0001-5445-8357</orcidid><orcidid>https://orcid.org/0000-0001-8067-4766</orcidid><orcidid>https://orcid.org/0000-0002-1103-5300</orcidid><orcidid>https://orcid.org/0000-0002-7675-3864</orcidid><orcidid>https://orcid.org/0000-0001-6757-0436</orcidid></search><sort><creationdate>20241212</creationdate><title>Covalent Inhibitors of KEAP1 with Exquisite Selectivity</title><author>Fejes, Imre ; Markacz, Piroska ; Tatai, Janos ; Rudas, Monika ; Dunkel, Petra ; Gyuris, Mario ; Nyerges, Miklos ; Provost, Nicolas ; Duvivier, Valérie ; Delerive, Philippe ; Martiny, Virginie ; Bristiel, Alexandra ; Vidal, Brice ; Richardson, William ; Rothweiler, Elisabeth M. ; Tranberg-Jensen, Jeppe ; Manning, Charlotte E. ; Sweeney, Melissa N. ; Chalk, Rod ; Huber, Kilian V. M. ; Bullock, Alex N. ; Herner, Andras ; Seedorf, Klaus ; Vinson, Cedric ; Weber, Csaba ; Kotschy, Andras</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a283t-6079019c6d20316aad78fd7481dc236b2136cf36b841a2c19e83ddfcc1d24f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Crystallography, X-Ray</topic><topic>Humans</topic><topic>Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors</topic><topic>Kelch-Like ECH-Associated Protein 1 - metabolism</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>NF-E2-Related Factor 2 - antagonists & inhibitors</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fejes, Imre</creatorcontrib><creatorcontrib>Markacz, Piroska</creatorcontrib><creatorcontrib>Tatai, Janos</creatorcontrib><creatorcontrib>Rudas, Monika</creatorcontrib><creatorcontrib>Dunkel, Petra</creatorcontrib><creatorcontrib>Gyuris, Mario</creatorcontrib><creatorcontrib>Nyerges, Miklos</creatorcontrib><creatorcontrib>Provost, Nicolas</creatorcontrib><creatorcontrib>Duvivier, Valérie</creatorcontrib><creatorcontrib>Delerive, Philippe</creatorcontrib><creatorcontrib>Martiny, Virginie</creatorcontrib><creatorcontrib>Bristiel, Alexandra</creatorcontrib><creatorcontrib>Vidal, Brice</creatorcontrib><creatorcontrib>Richardson, William</creatorcontrib><creatorcontrib>Rothweiler, Elisabeth M.</creatorcontrib><creatorcontrib>Tranberg-Jensen, Jeppe</creatorcontrib><creatorcontrib>Manning, Charlotte E.</creatorcontrib><creatorcontrib>Sweeney, Melissa N.</creatorcontrib><creatorcontrib>Chalk, Rod</creatorcontrib><creatorcontrib>Huber, Kilian V. M.</creatorcontrib><creatorcontrib>Bullock, Alex N.</creatorcontrib><creatorcontrib>Herner, Andras</creatorcontrib><creatorcontrib>Seedorf, Klaus</creatorcontrib><creatorcontrib>Vinson, Cedric</creatorcontrib><creatorcontrib>Weber, Csaba</creatorcontrib><creatorcontrib>Kotschy, Andras</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fejes, Imre</au><au>Markacz, Piroska</au><au>Tatai, Janos</au><au>Rudas, Monika</au><au>Dunkel, Petra</au><au>Gyuris, Mario</au><au>Nyerges, Miklos</au><au>Provost, Nicolas</au><au>Duvivier, Valérie</au><au>Delerive, Philippe</au><au>Martiny, Virginie</au><au>Bristiel, Alexandra</au><au>Vidal, Brice</au><au>Richardson, William</au><au>Rothweiler, Elisabeth M.</au><au>Tranberg-Jensen, Jeppe</au><au>Manning, Charlotte E.</au><au>Sweeney, Melissa N.</au><au>Chalk, Rod</au><au>Huber, Kilian V. M.</au><au>Bullock, Alex N.</au><au>Herner, Andras</au><au>Seedorf, Klaus</au><au>Vinson, Cedric</au><au>Weber, Csaba</au><au>Kotschy, Andras</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Covalent Inhibitors of KEAP1 with Exquisite Selectivity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-12-12</date><risdate>2024</risdate><volume>67</volume><issue>23</issue><spage>21208</spage><epage>21222</epage><pages>21208-21222</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>39572012</pmid><doi>10.1021/acs.jmedchem.4c02019</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-6866-3957</orcidid><orcidid>https://orcid.org/0000-0001-5445-8357</orcidid><orcidid>https://orcid.org/0000-0001-8067-4766</orcidid><orcidid>https://orcid.org/0000-0002-1103-5300</orcidid><orcidid>https://orcid.org/0000-0002-7675-3864</orcidid><orcidid>https://orcid.org/0000-0001-6757-0436</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2024-12, Vol.67 (23), p.21208-21222 |
| issn | 0022-2623 1520-4804 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11647895 |
| source | ACS Publications; MEDLINE |
| subjects | Animals Crystallography, X-Ray Humans Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors Kelch-Like ECH-Associated Protein 1 - metabolism Mice Models, Molecular NF-E2-Related Factor 2 - antagonists & inhibitors NF-E2-Related Factor 2 - metabolism Structure-Activity Relationship |
| title | Covalent Inhibitors of KEAP1 with Exquisite Selectivity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T01%3A38%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Covalent%20Inhibitors%20of%20KEAP1%20with%20Exquisite%20Selectivity&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Fejes,%20Imre&rft.date=2024-12-12&rft.volume=67&rft.issue=23&rft.spage=21208&rft.epage=21222&rft.pages=21208-21222&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.4c02019&rft_dat=%3Cproquest_pubme%3E3131851050%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3131851050&rft_id=info:pmid/39572012&rfr_iscdi=true |