Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid.
Léa MélinShuay AbdullayevAhmed FnaicheVictoria VuNarjara González SuárezHong ZengMagdalena M SzewczykFengling LiGuillermo SenisterraAbdellah Allali-HassaniIrene ChauAiping DongSimon WooBorhane AnnabiLevon HalabelianSteven R LaPlanteMasoud VedadiDalia Barsyte-LovejoyVijayaratnam SanthakumarAlexandre GagnonPublished in: ChemMedChem (2021)
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.
Keyphrases
- transcription factor
- poor prognosis
- small molecule
- cell migration
- gene expression
- single cell
- cell therapy
- signaling pathway
- squamous cell carcinoma
- cell proliferation
- stem cells
- dna binding
- long non coding rna
- mesenchymal stem cells
- bone marrow
- dna methylation
- cell death
- breast cancer cells
- high intensity
- mass spectrometry
- genome wide analysis
- squamous cell