Cancers, Vol. 10, Pages 140: Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

Cancers, Vol. 10, Pages 140: Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

Cancers doi: 10.3390/cancers10050140

Authors: Floriane Gibault Mathilde Coevoet Manon Sturbaut Amaury Farce Nicolas Renault Frédéric Allemand Jean-François Guichou Anne-Sophie Drucbert Catherine Foulon Romain Magnez Xavier Thuru Matthieu Corvaisier Guillemette Huet Philippe Chavatte Patricia Melnyk Fabrice Bailly Philippe Cotelle

Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-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 hYAP50–71-hTEAD1209–426 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.

https://ift.tt/2ruxn1P