Cancers 2018, 10(5), 140; https://doi.org/10.3390/cancers10050140
Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface
Floriane Gibault 1, Mathilde Coevoet 1, Manon Sturbaut 1, Amaury Farce 2, Nicolas Renault 2, Frédéric Allemand 3, Jean-François Guichou 3, Anne-Sophie Drucbert 4, Catherine Foulon 4, Romain Magnez 1, Xavier Thuru 1, Matthieu Corvaisier 1, Guillemette Huet 1, Philippe Chavatte 2, Patricia Melnyk 1
, Fabrice Bailly 1,* and Philippe Cotelle 1,5
, Fabrice Bailly 1,* and Philippe Cotelle 1,5
1
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France
2
University of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France
3
University of Montpellier, CNRS-UMR5048, INSERM-U1054, Centre de Biochimie Structurale, 29 rue de Navacelles, F-34090 Montpellier, France
4
University of Lille, CHU Lille, Plate-forme d’Interactions Moléculaires, F-59000 Lille, France
5
ENSCL, F-59000 Lille, France
*
Author to whom correspondence should be addressed.
Received: 24 April 2018 / Revised: 3 May 2018 / Accepted: 4 May 2018 / Published: 8 May 2018
(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)
Abstract
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. View Full-TextKeywords:
protein-protein interaction; YAP-TEAD disruption; molecular docking; binding assays; anticancer
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Gibault, F.; Coevoet, M.; Sturbaut, M.; Farce, A.; Renault, N.; Allemand, F.; Guichou, J.-F.; Drucbert, A.-S.; Foulon, C.; Magnez, R.; Thuru, X.; Corvaisier, M.; Huet, G.; Chavatte, P.; Melnyk, P.; Bailly, F.; Cotelle, P. Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface. Cancers 2018, 10, 140.
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