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Cancers (Basel). 2018 May 8;10(5). pii: E140. doi: 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.

Author information

1
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. floriane.gibault@ed.univ-lille1.fr.
2
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. mathilde.coevoet@inserm.fr.
3
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. manon.sturbaut@etu.univ-lille2.fr.
4
University of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France. amaury.farce-2@univ-lille2.fr.
5
University of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France. nicolas.renault-3@univ-lille2.fr.
6
University of Montpellier, CNRS-UMR5048, INSERM-U1054, Centre de Biochimie Structurale, 29 rue de Navacelles, F-34090 Montpellier, France. frederic.allemand@cbs.cnrs.fr.
7
University of Montpellier, CNRS-UMR5048, INSERM-U1054, Centre de Biochimie Structurale, 29 rue de Navacelles, F-34090 Montpellier, France. guichou@cbs.cnrs.fr.
8
University of Lille, CHU Lille, Plate-forme d'Interactions Moléculaires, F-59000 Lille, France. anne-sophie.drucbert@univ-lille2.fr.
9
University of Lille, CHU Lille, Plate-forme d'Interactions Moléculaires, F-59000 Lille, France. catherine.foulon@univ-lille2.fr.
10
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. romain.magnez@inserm.fr.
11
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. xavier.thuru@inserm.fr.
12
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. matthieu.corvaisier@inserm.fr.
13
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. guillemette.huet@inserm.fr.
14
University of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France. philippe.chavatte@univ-lille2.fr.
15
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. patricia.melnyk@univ-lille2.fr.
16
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. fabrice.bailly@univ-lille1.fr.
17
University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. philippe.cotelle@univ-lille1.fr.
18
ENSCL, F-59000 Lille, France. philippe.cotelle@univ-lille1.fr.

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.

KEYWORDS:

YAP-TEAD disruption; anticancer; binding assays; molecular docking; protein-protein interaction

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