Development of LM98, a Small‐Molecule TEAD Inhibitor Derived from Flufenamic Acid
The YAP‐TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated...
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| Veröffentlicht in: | ChemMedChem 2021-10, Vol.16 (19), p.2982-3002 |
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| creator | Mélin, Léa Abdullayev, Shuay Fnaiche, Ahmed Vu, Victoria González Suárez, Narjara Zeng, Hong Szewczyk, Magdalena M. Li, Fengling Senisterra, Guillermo Allali‐Hassani, Abdellah Chau, Irene Dong, Aiping Woo, Simon Annabi, Borhane Halabelian, Levon LaPlante, Steven R. Vedadi, Masoud Barsyte‐Lovejoy, Dalia Santhakumar, Vijayaratnam Gagnon, Alexandre |
| description | The YAP‐TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti‐cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP‐TEAD transcriptional activity. Binding of LM98 to TEAD was supported by 19F‐NMR studies while co‐crystallization experiments confirmed that LM98 is anchored within the palmitic acid pocket of TEAD. LM98 reduces the expression of CTGF and Cyr61, inhibits MDA‐MB‐231 breast cancer cell migration and arrests cell cycling in the S phase during cell division.
Fusion chemistry: We report the design and development of LM98, a reversible TEAD inhibitor that originates from the fusion of flufenamic acid and palmitic acid. LM98 binds in the palmitic acid pocket of TEAD, preventing its autopalmitoylation and reducing the expression of associated genes. LM98 reduces TEAD activation, inhibits breast cancer cell migration and arrests cells in the S phase. Extensive SAR studies revealed new opportunities for future medicinal chemistry activities within this series. |
| doi_str_mv | 10.1002/cmdc.202100432 |
| format | Article |
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Fusion chemistry: We report the design and development of LM98, a reversible TEAD inhibitor that originates from the fusion of flufenamic acid and palmitic acid. LM98 binds in the palmitic acid pocket of TEAD, preventing its autopalmitoylation and reducing the expression of associated genes. LM98 reduces TEAD activation, inhibits breast cancer cell migration and arrests cells in the S phase. Extensive SAR studies revealed new opportunities for future medicinal chemistry activities within this series.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.202100432</identifier><identifier>PMID: 34164919</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Breast cancer ; Cancer ; Cell Cycle - drug effects ; Cell division ; Cell migration ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Connective tissue growth factor ; Crystallization ; CYR61 protein ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Flufenamic acid ; Flufenamic Acid - chemistry ; Flufenamic Acid - pharmacology ; Gene expression ; Genes ; Hippo pathway ; Humans ; Molecular Structure ; NMR ; Nuclear magnetic resonance ; Palmitic acid ; S phase ; SAR ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Structure-Activity Relationship ; TEA Domain Transcription Factors - antagonists & inhibitors ; TEA Domain Transcription Factors - metabolism ; TEAD ; Tumor Cells, Cultured ; Yes-associated protein</subject><ispartof>ChemMedChem, 2021-10, Vol.16 (19), p.2982-3002</ispartof><rights>2021 Wiley‐VCH GmbH</rights><rights>2021 Wiley-VCH GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3732-560ae1a05116475be5692462c8b10e4c832d55972db55a5d05c614be1c2a15743</citedby><cites>FETCH-LOGICAL-c3732-560ae1a05116475be5692462c8b10e4c832d55972db55a5d05c614be1c2a15743</cites><orcidid>0000-0002-0242-0936</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.202100432$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.202100432$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34164919$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mélin, Léa</creatorcontrib><creatorcontrib>Abdullayev, Shuay</creatorcontrib><creatorcontrib>Fnaiche, Ahmed</creatorcontrib><creatorcontrib>Vu, Victoria</creatorcontrib><creatorcontrib>González Suárez, Narjara</creatorcontrib><creatorcontrib>Zeng, Hong</creatorcontrib><creatorcontrib>Szewczyk, Magdalena M.</creatorcontrib><creatorcontrib>Li, Fengling</creatorcontrib><creatorcontrib>Senisterra, Guillermo</creatorcontrib><creatorcontrib>Allali‐Hassani, Abdellah</creatorcontrib><creatorcontrib>Chau, Irene</creatorcontrib><creatorcontrib>Dong, Aiping</creatorcontrib><creatorcontrib>Woo, Simon</creatorcontrib><creatorcontrib>Annabi, Borhane</creatorcontrib><creatorcontrib>Halabelian, Levon</creatorcontrib><creatorcontrib>LaPlante, Steven R.</creatorcontrib><creatorcontrib>Vedadi, Masoud</creatorcontrib><creatorcontrib>Barsyte‐Lovejoy, Dalia</creatorcontrib><creatorcontrib>Santhakumar, Vijayaratnam</creatorcontrib><creatorcontrib>Gagnon, Alexandre</creatorcontrib><title>Development of LM98, a Small‐Molecule TEAD Inhibitor Derived from Flufenamic Acid</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>The YAP‐TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti‐cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP‐TEAD transcriptional activity. Binding of LM98 to TEAD was supported by 19F‐NMR studies while co‐crystallization experiments confirmed that LM98 is anchored within the palmitic acid pocket of TEAD. LM98 reduces the expression of CTGF and Cyr61, inhibits MDA‐MB‐231 breast cancer cell migration and arrests cell cycling in the S phase during cell division.
Fusion chemistry: We report the design and development of LM98, a reversible TEAD inhibitor that originates from the fusion of flufenamic acid and palmitic acid. LM98 binds in the palmitic acid pocket of TEAD, preventing its autopalmitoylation and reducing the expression of associated genes. LM98 reduces TEAD activation, inhibits breast cancer cell migration and arrests cells in the S phase. Extensive SAR studies revealed new opportunities for future medicinal chemistry activities within this series.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell Cycle - drug effects</subject><subject>Cell division</subject><subject>Cell migration</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Connective tissue growth factor</subject><subject>Crystallization</subject><subject>CYR61 protein</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Flufenamic acid</subject><subject>Flufenamic Acid - chemistry</subject><subject>Flufenamic Acid - pharmacology</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Hippo pathway</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Palmitic acid</subject><subject>S phase</subject><subject>SAR</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>TEA Domain Transcription Factors - antagonists & inhibitors</subject><subject>TEA Domain Transcription Factors - metabolism</subject><subject>TEAD</subject><subject>Tumor Cells, Cultured</subject><subject>Yes-associated protein</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkL9OwzAQhy0EoqWwMiJLrKTYjp0_Y5W0UKkVQ8tsOc5FpEri4jRF3XgEnpEnwVVLGfFyPum7350-hG4pGVJC2KOucz1khLmG--wM9WkUEC-kUXh--odxD1217cohPKLRJer5nAY8pnEfLVLYQmXWNTQbbAo8m8fRA1Z4Uauq-v78mpsKdFcBXo5HKZ42b2VWbozFKdhyCzkurKnxpOoKaFRdajzSZX6NLgpVtXBzrAP0Ohkvk2dv9vI0TUYzT_uhzzwREAVUEUHdMaHIQAQx4wHTUUYJcB35LBciDlmeCaFEToQOKM-AaqaoCLk_QPeH3LU17x20G7kynW3cSslEGPs0cM9RwwOlrWlbC4Vc27JWdicpkXuHcu9Qnhy6gbtjbJfVkJ_wX2kOiA_AR1nB7p84mczT5C_8ByhReyo</recordid><startdate>20211006</startdate><enddate>20211006</enddate><creator>Mélin, Léa</creator><creator>Abdullayev, Shuay</creator><creator>Fnaiche, Ahmed</creator><creator>Vu, Victoria</creator><creator>González Suárez, Narjara</creator><creator>Zeng, Hong</creator><creator>Szewczyk, Magdalena M.</creator><creator>Li, Fengling</creator><creator>Senisterra, Guillermo</creator><creator>Allali‐Hassani, Abdellah</creator><creator>Chau, Irene</creator><creator>Dong, Aiping</creator><creator>Woo, Simon</creator><creator>Annabi, Borhane</creator><creator>Halabelian, Levon</creator><creator>LaPlante, Steven R.</creator><creator>Vedadi, Masoud</creator><creator>Barsyte‐Lovejoy, Dalia</creator><creator>Santhakumar, Vijayaratnam</creator><creator>Gagnon, Alexandre</creator><general>Wiley Subscription Services, Inc</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>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0002-0242-0936</orcidid></search><sort><creationdate>20211006</creationdate><title>Development of LM98, a Small‐Molecule TEAD Inhibitor Derived from Flufenamic Acid</title><author>Mélin, Léa ; Abdullayev, Shuay ; Fnaiche, Ahmed ; Vu, Victoria ; González Suárez, Narjara ; Zeng, Hong ; Szewczyk, Magdalena M. ; Li, Fengling ; Senisterra, Guillermo ; Allali‐Hassani, Abdellah ; Chau, Irene ; Dong, Aiping ; Woo, Simon ; Annabi, Borhane ; Halabelian, Levon ; LaPlante, Steven R. ; Vedadi, Masoud ; Barsyte‐Lovejoy, Dalia ; Santhakumar, Vijayaratnam ; Gagnon, Alexandre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3732-560ae1a05116475be5692462c8b10e4c832d55972db55a5d05c614be1c2a15743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cell Cycle - drug effects</topic><topic>Cell division</topic><topic>Cell migration</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Connective tissue growth factor</topic><topic>Crystallization</topic><topic>CYR61 protein</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Flufenamic acid</topic><topic>Flufenamic Acid - chemistry</topic><topic>Flufenamic Acid - pharmacology</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Hippo pathway</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Palmitic acid</topic><topic>S phase</topic><topic>SAR</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>TEA Domain Transcription Factors - antagonists & inhibitors</topic><topic>TEA Domain Transcription Factors - metabolism</topic><topic>TEAD</topic><topic>Tumor Cells, Cultured</topic><topic>Yes-associated protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mélin, Léa</creatorcontrib><creatorcontrib>Abdullayev, Shuay</creatorcontrib><creatorcontrib>Fnaiche, Ahmed</creatorcontrib><creatorcontrib>Vu, Victoria</creatorcontrib><creatorcontrib>González Suárez, Narjara</creatorcontrib><creatorcontrib>Zeng, Hong</creatorcontrib><creatorcontrib>Szewczyk, Magdalena M.</creatorcontrib><creatorcontrib>Li, Fengling</creatorcontrib><creatorcontrib>Senisterra, Guillermo</creatorcontrib><creatorcontrib>Allali‐Hassani, Abdellah</creatorcontrib><creatorcontrib>Chau, Irene</creatorcontrib><creatorcontrib>Dong, Aiping</creatorcontrib><creatorcontrib>Woo, Simon</creatorcontrib><creatorcontrib>Annabi, Borhane</creatorcontrib><creatorcontrib>Halabelian, Levon</creatorcontrib><creatorcontrib>LaPlante, Steven R.</creatorcontrib><creatorcontrib>Vedadi, Masoud</creatorcontrib><creatorcontrib>Barsyte‐Lovejoy, Dalia</creatorcontrib><creatorcontrib>Santhakumar, Vijayaratnam</creatorcontrib><creatorcontrib>Gagnon, Alexandre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mélin, Léa</au><au>Abdullayev, Shuay</au><au>Fnaiche, Ahmed</au><au>Vu, Victoria</au><au>González Suárez, Narjara</au><au>Zeng, Hong</au><au>Szewczyk, Magdalena M.</au><au>Li, Fengling</au><au>Senisterra, Guillermo</au><au>Allali‐Hassani, Abdellah</au><au>Chau, Irene</au><au>Dong, Aiping</au><au>Woo, Simon</au><au>Annabi, Borhane</au><au>Halabelian, Levon</au><au>LaPlante, Steven R.</au><au>Vedadi, Masoud</au><au>Barsyte‐Lovejoy, Dalia</au><au>Santhakumar, Vijayaratnam</au><au>Gagnon, Alexandre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of LM98, a Small‐Molecule TEAD Inhibitor Derived from Flufenamic Acid</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2021-10-06</date><risdate>2021</risdate><volume>16</volume><issue>19</issue><spage>2982</spage><epage>3002</epage><pages>2982-3002</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>The YAP‐TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti‐cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP‐TEAD transcriptional activity. Binding of LM98 to TEAD was supported by 19F‐NMR studies while co‐crystallization experiments confirmed that LM98 is anchored within the palmitic acid pocket of TEAD. LM98 reduces the expression of CTGF and Cyr61, inhibits MDA‐MB‐231 breast cancer cell migration and arrests cell cycling in the S phase during cell division.
Fusion chemistry: We report the design and development of LM98, a reversible TEAD inhibitor that originates from the fusion of flufenamic acid and palmitic acid. LM98 binds in the palmitic acid pocket of TEAD, preventing its autopalmitoylation and reducing the expression of associated genes. LM98 reduces TEAD activation, inhibits breast cancer cell migration and arrests cells in the S phase. Extensive SAR studies revealed new opportunities for future medicinal chemistry activities within this series.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34164919</pmid><doi>10.1002/cmdc.202100432</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0002-0242-0936</orcidid></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Breast cancer Cancer Cell Cycle - drug effects Cell division Cell migration Cell Proliferation - drug effects Cell Survival - drug effects Connective tissue growth factor Crystallization CYR61 protein Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Flufenamic acid Flufenamic Acid - chemistry Flufenamic Acid - pharmacology Gene expression Genes Hippo pathway Humans Molecular Structure NMR Nuclear magnetic resonance Palmitic acid S phase SAR Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship TEA Domain Transcription Factors - antagonists & inhibitors TEA Domain Transcription Factors - metabolism TEAD Tumor Cells, Cultured Yes-associated protein |
| title | Development of LM98, a Small‐Molecule TEAD Inhibitor Derived from Flufenamic Acid |
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