Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid.
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.
Key words
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