Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

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

doi:10.3390/cancers10050140

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Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

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Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

Floriane Gibault, Mathilde Coevoet, Manon Sturbaut, Amaury Farce, Nicolas Renault, Frédéric Allemand, Jean-François Guichou, Anne Sophie Drucbert, Catherine Foulon, Romain Magnez, …

Cancers, Vol.10(5)

2018

DOI: https://doi.org/10.3390/cancers10050140

PMID: 29738494

Abstract

YAP-TEAD disruption

anticancer

protein-protein interaction

molecular docking

binding assays

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 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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Title: Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface
Creators - without role: Floriane Gibault - Université de Lille
Mathilde Coevoet - Université de Lille
Manon Sturbaut - Université de Lille
Amaury Farce - Université de Lille
Nicolas Renault - Université de Lille
Frédéric Allemand - Université de Montpellier, Centre de Biologie Structurale - CBS
Jean-François Guichou - Université de Montpellier, Centre de Biologie Structurale - CBS
Anne Sophie Drucbert - Centre Hospitalier Universitaire de Lille
Catherine Foulon - Centre Hospitalier Universitaire de Lille
Romain Magnez - Université de Lille
Xavier Thuru - Université de Lille
Mathieu Corvaisier - Centre de Recherche Jean Pierre Aubert
Guillemette Huet - Centre de Recherche Jean Pierre Aubert
Philippe Chavatte - Université de Lille
Patricia Melnyk - Centre de Recherche Jean Pierre Aubert
Fabrice Bailly - Université de Lille
Philippe Cotelle - Centre de Recherche Jean Pierre Aubert
Publication Details: Cancers, Vol.10(5)
Identifiers: 9947104809311
Academic Unit: Centre de Biologie Structurale - CBS
Language: English
Resource Type: Journal article
Local Fields: hal-02060686