期刊
CANCERS
卷 10, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/cancers10050140
关键词
protein-protein interaction; YAP-TEAD disruption; molecular docking; binding assays; anticancer
类别
资金
- le Ministere de l'Education et de la Recherche
- SIRIC OncoLille and le Canceropole Nord-Ouest [2016/09]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]
Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Omega-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP(50-71)-hTEAD1(209-426) complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD. Four different chemical families have been identified and evaluated using biophysical techniques (thermal shift assay, microscale thermophoresis) and in cellulo assays (luciferase activity in transfected HEK293 cells, RTqPCR in MDA-MB231 cells). A first promising hit with micromolar inhibition in the luciferase gene reporter assay was discovered. This hit also decreased mRNA levels of TEAD target genes.
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