Mélin, Léa; Abdullayev, Shuay; Fnaiche, Ahmed; Vu, Victoria; González Suárez, Narjara; Zeng, Hong; Szewczyk, Magdalena; Li, Fengling; Senisterra, Guillermo; Allali-Hassani, Abdellah; Chau, Irene; Dong, Aiping; Woo, Simon; Annabi, Borhane; Halabelian, Levon; Laplante, Steven 
ORCID: https://orcid.org/0000-0003-2835-5789; Vedadi, Masoud; Barsyte-Lovejoy, Dalia; Santhakumar, Vijayaratnam et Gagnon, Alexandre
(2021).
Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid
ChemMedChem
, vol. 16
, nº 19.
pp. 2982-3002.
DOI: 10.1002/cmdc.202100432.
Résumé
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.
| Type de document: | Article |
|---|---|
| Mots-clés libres: | Flufenamic acid; Hippo pathway; SAR; TEAD; palmitic acid |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 30 juin 2022 13:58 |
| Dernière modification: | 30 juin 2022 13:58 |
| URI: | https://espace.inrs.ca/id/eprint/12388 |
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