Your browser doesn't support javascript.
loading
Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid.
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.
Affiliation
  • Mélin L; Département de chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
  • Abdullayev S; Département de chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
  • Fnaiche A; Département de chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
  • Vu V; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • González Suárez N; Département de chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
  • Zeng H; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Szewczyk MM; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Li F; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Senisterra G; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Allali-Hassani A; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Chau I; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Dong A; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Woo S; INRS-Centre Armand Frappier Santé Biotechnologie, Université du Québec, 531 Boulevard des Prairies, Laval, QC, H7V 1B7, Canada.
  • Annabi B; Département de chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
  • Halabelian L; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • LaPlante SR; INRS-Centre Armand Frappier Santé Biotechnologie, Université du Québec, 531 Boulevard des Prairies, Laval, QC, H7V 1B7, Canada.
  • Vedadi M; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Barsyte-Lovejoy D; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1 A8, Canada.
  • Santhakumar V; Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  • Gagnon A; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1 A8, Canada.
ChemMedChem ; 16(19): 2982-3002, 2021 10 06.
Article in En | MEDLINE | ID: mdl-34164919
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 19 F-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.
Subject(s)
Key words
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Flufenamic Acid / Small Molecule Libraries / TEA Domain Transcription Factors / Antineoplastic Agents Limits: Humans Language: En Journal: ChemMedChem Journal subject: FARMACOLOGIA / QUIMICA Year: 2021 Type: Article Affiliation country: Canada
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Flufenamic Acid / Small Molecule Libraries / TEA Domain Transcription Factors / Antineoplastic Agents Limits: Humans Language: En Journal: ChemMedChem Journal subject: FARMACOLOGIA / QUIMICA Year: 2021 Type: Article Affiliation country: Canada