Towards the design of ligands of the internal pocket TEADs C-terminal domain
The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and...
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| Veröffentlicht in: | European journal of medicinal chemistry 2025-01, Vol.282, p.117026, Article 117026 |
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| container_title | European journal of medicinal chemistry |
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| creator | Toulotte, Florine Coevoet, Mathilde Liberelle, Maxime Bailly, Fabrice Zagiel, Benjamin Gelin, Muriel Allemand, Frédéric Fourquet, Patrick Melnyk, Patricia Guichou, Jean-François Cotelle, Philippe |
| description | The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.
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•Characterization and optimization of covalent and non-covalent ligands of the internal pocket of TEAD.•Best compounds alter the expression of YAP/TAZ-TEAD target genes - CTGF, Cyr61, AXL and BIRC5.•Best compounds inhibit cell proliferation of breast cancer cells. |
| doi_str_mv | 10.1016/j.ejmech.2024.117026 |
| format | Article |
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[Display omitted]
•Characterization and optimization of covalent and non-covalent ligands of the internal pocket of TEAD.•Best compounds alter the expression of YAP/TAZ-TEAD target genes - CTGF, Cyr61, AXL and BIRC5.•Best compounds inhibit cell proliferation of breast cancer cells.</description><identifier>ISSN: 0223-5234</identifier><identifier>ISSN: 1768-3254</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2024.117026</identifier><identifier>PMID: 39571457</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Breast cancer proliferation inhibition ; Cell Line, Tumor ; Cell Proliferation - drug effects ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - chemistry ; DNA-Binding Proteins - metabolism ; Dose-Response Relationship, Drug ; Drug Design ; Drug Screening Assays, Antitumor ; Hippo pathway ; Humans ; Ligands ; Models, Molecular ; Molecular Structure ; Protein Domains - drug effects ; Structure-Activity Relationship ; TEA Domain Transcription Factors - metabolism ; TEAD inhibition ; TEAD internal pocket ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - metabolism ; YAP-Signaling Proteins - metabolism</subject><ispartof>European journal of medicinal chemistry, 2025-01, Vol.282, p.117026, Article 117026</ispartof><rights>2024</rights><rights>Copyright © 2024. Published by Elsevier Masson SAS.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c241t-6ddf0d08d8d1016afd75edb89b775539c66f2de25a4a70ea965094bb75e688d83</cites><orcidid>0000-0003-0924-0433 ; 0000-0003-1320-8663 ; 0000-0002-9555-3446 ; 0000-0003-0396-6145 ; 0000-0001-7529-6676 ; 0000-0002-7699-3235 ; 0000-0001-9681-9309 ; 0000-0002-5547-0240</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523424009085$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39571457$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Toulotte, Florine</creatorcontrib><creatorcontrib>Coevoet, Mathilde</creatorcontrib><creatorcontrib>Liberelle, Maxime</creatorcontrib><creatorcontrib>Bailly, Fabrice</creatorcontrib><creatorcontrib>Zagiel, Benjamin</creatorcontrib><creatorcontrib>Gelin, Muriel</creatorcontrib><creatorcontrib>Allemand, Frédéric</creatorcontrib><creatorcontrib>Fourquet, Patrick</creatorcontrib><creatorcontrib>Melnyk, Patricia</creatorcontrib><creatorcontrib>Guichou, Jean-François</creatorcontrib><creatorcontrib>Cotelle, Philippe</creatorcontrib><title>Towards the design of ligands of the internal pocket TEADs C-terminal domain</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.
[Display omitted]
•Characterization and optimization of covalent and non-covalent ligands of the internal pocket of TEAD.•Best compounds alter the expression of YAP/TAZ-TEAD target genes - CTGF, Cyr61, AXL and BIRC5.•Best compounds inhibit cell proliferation of breast cancer cells.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Breast cancer proliferation inhibition</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - chemistry</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Hippo pathway</subject><subject>Humans</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Protein Domains - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>TEA Domain Transcription Factors - metabolism</subject><subject>TEAD inhibition</subject><subject>TEAD internal pocket</subject><subject>Transcription Factors - antagonists & inhibitors</subject><subject>Transcription Factors - metabolism</subject><subject>YAP-Signaling Proteins - metabolism</subject><issn>0223-5234</issn><issn>1768-3254</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0EoqXwDxDKkUuC7cR2ckGqSnlIlbiUs-XYm9Ylj2KnIP49jlI4clpr_M2OdhC6JjghmPC7XQK7BvQ2oZhmCSECU36CpkTwPE4py07RFFOaxoym2QRdeL_DGDOO8TmapAUTJGNiilbr7ks546N-C5EBbzdt1FVRbTeqDWp4Dh-27cG1qo72nX6HPlov5w8-WsRBbeygm65Rtr1EZ5WqPVwd5wy9PS7Xi-d49fr0spivYk0z0sfcmAobnJvcDJeoyggGpsyLUgjG0kJzXlEDlKlMCQyq4AwXWVkGiufBlc7Q7bh377qPA_heNtZrqGvVQnfwMiUpyRmlBQtoNqLadd47qOTe2Ua5b0mwHNLlTo49yqFHOfYYbDfHhEPZgPkz_RYXgPsRgHDnpwUnvbbQajDWge6l6ez_CT-SLoR6</recordid><startdate>20250115</startdate><enddate>20250115</enddate><creator>Toulotte, Florine</creator><creator>Coevoet, Mathilde</creator><creator>Liberelle, Maxime</creator><creator>Bailly, Fabrice</creator><creator>Zagiel, Benjamin</creator><creator>Gelin, Muriel</creator><creator>Allemand, Frédéric</creator><creator>Fourquet, Patrick</creator><creator>Melnyk, Patricia</creator><creator>Guichou, Jean-François</creator><creator>Cotelle, Philippe</creator><general>Elsevier Masson SAS</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/0000-0003-0924-0433</orcidid><orcidid>https://orcid.org/0000-0003-1320-8663</orcidid><orcidid>https://orcid.org/0000-0002-9555-3446</orcidid><orcidid>https://orcid.org/0000-0003-0396-6145</orcidid><orcidid>https://orcid.org/0000-0001-7529-6676</orcidid><orcidid>https://orcid.org/0000-0002-7699-3235</orcidid><orcidid>https://orcid.org/0000-0001-9681-9309</orcidid><orcidid>https://orcid.org/0000-0002-5547-0240</orcidid></search><sort><creationdate>20250115</creationdate><title>Towards the design of ligands of the internal pocket TEADs C-terminal domain</title><author>Toulotte, Florine ; Coevoet, Mathilde ; Liberelle, Maxime ; Bailly, Fabrice ; Zagiel, Benjamin ; Gelin, Muriel ; Allemand, Frédéric ; Fourquet, Patrick ; Melnyk, Patricia ; Guichou, Jean-François ; Cotelle, Philippe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c241t-6ddf0d08d8d1016afd75edb89b775539c66f2de25a4a70ea965094bb75e688d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Breast cancer proliferation inhibition</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>DNA-Binding Proteins - antagonists & inhibitors</topic><topic>DNA-Binding Proteins - chemistry</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Hippo pathway</topic><topic>Humans</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Protein Domains - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>TEA Domain Transcription Factors - metabolism</topic><topic>TEAD inhibition</topic><topic>TEAD internal pocket</topic><topic>Transcription Factors - antagonists & inhibitors</topic><topic>Transcription Factors - metabolism</topic><topic>YAP-Signaling Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Toulotte, Florine</creatorcontrib><creatorcontrib>Coevoet, Mathilde</creatorcontrib><creatorcontrib>Liberelle, Maxime</creatorcontrib><creatorcontrib>Bailly, Fabrice</creatorcontrib><creatorcontrib>Zagiel, Benjamin</creatorcontrib><creatorcontrib>Gelin, Muriel</creatorcontrib><creatorcontrib>Allemand, Frédéric</creatorcontrib><creatorcontrib>Fourquet, Patrick</creatorcontrib><creatorcontrib>Melnyk, Patricia</creatorcontrib><creatorcontrib>Guichou, Jean-François</creatorcontrib><creatorcontrib>Cotelle, Philippe</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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Toulotte, Florine</au><au>Coevoet, Mathilde</au><au>Liberelle, Maxime</au><au>Bailly, Fabrice</au><au>Zagiel, Benjamin</au><au>Gelin, Muriel</au><au>Allemand, Frédéric</au><au>Fourquet, Patrick</au><au>Melnyk, Patricia</au><au>Guichou, Jean-François</au><au>Cotelle, Philippe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Towards the design of ligands of the internal pocket TEADs C-terminal domain</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2025-01-15</date><risdate>2025</risdate><volume>282</volume><spage>117026</spage><pages>117026-</pages><artnum>117026</artnum><issn>0223-5234</issn><issn>1768-3254</issn><eissn>1768-3254</eissn><abstract>The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.
[Display omitted]
•Characterization and optimization of covalent and non-covalent ligands of the internal pocket of TEAD.•Best compounds alter the expression of YAP/TAZ-TEAD target genes - CTGF, Cyr61, AXL and BIRC5.•Best compounds inhibit cell proliferation of breast cancer cells.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>39571457</pmid><doi>10.1016/j.ejmech.2024.117026</doi><orcidid>https://orcid.org/0000-0003-0924-0433</orcidid><orcidid>https://orcid.org/0000-0003-1320-8663</orcidid><orcidid>https://orcid.org/0000-0002-9555-3446</orcidid><orcidid>https://orcid.org/0000-0003-0396-6145</orcidid><orcidid>https://orcid.org/0000-0001-7529-6676</orcidid><orcidid>https://orcid.org/0000-0002-7699-3235</orcidid><orcidid>https://orcid.org/0000-0001-9681-9309</orcidid><orcidid>https://orcid.org/0000-0002-5547-0240</orcidid></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2025-01, Vol.282, p.117026, Article 117026 |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Breast cancer proliferation inhibition Cell Line, Tumor Cell Proliferation - drug effects DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - chemistry DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Drug Design Drug Screening Assays, Antitumor Hippo pathway Humans Ligands Models, Molecular Molecular Structure Protein Domains - drug effects Structure-Activity Relationship TEA Domain Transcription Factors - metabolism TEAD inhibition TEAD internal pocket Transcription Factors - antagonists & inhibitors Transcription Factors - metabolism YAP-Signaling Proteins - metabolism |
| title | Towards the design of ligands of the internal pocket TEADs C-terminal domain |
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