Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-05-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/10/5/140 |
| _version_ | 1797706580614971392 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Floriane Gibault |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T05:53:25Z |
| format | Article |
| id | doaj.art-577e777214884ea1a55d9d4629a58796 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T05:53:25Z |
| publishDate | 2018-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-577e777214884ea1a55d9d4629a587962023-09-03T04:51:02ZengMDPI AGCancers2072-66942018-05-0110514010.3390/cancers10050140cancers10050140Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein InterfaceFloriane Gibault0Mathilde Coevoet1Manon Sturbaut2Amaury Farce3Nicolas Renault4Frédéric Allemand5Jean-François Guichou6Anne-Sophie Drucbert7Catherine Foulon8Romain Magnez9Xavier Thuru10Matthieu Corvaisier11Guillemette Huet12Philippe Chavatte13Patricia Melnyk14Fabrice Bailly15Philippe Cotelle16University of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, FranceUniversity of Montpellier, CNRS-UMR5048, INSERM-U1054, Centre de Biochimie Structurale, 29 rue de Navacelles, F-34090 Montpellier, FranceUniversity of Montpellier, CNRS-UMR5048, INSERM-U1054, Centre de Biochimie Structurale, 29 rue de Navacelles, F-34090 Montpellier, FranceUniversity of Lille, CHU Lille, Plate-forme d’Interactions Moléculaires, F-59000 Lille, FranceUniversity of Lille, CHU Lille, Plate-forme d’Interactions Moléculaires, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-U995 LIRIC-Lille Inflammation Research International Center, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceUniversity of Lille, CHU Lille, INSERM-UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, FranceIntrinsically 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.http://www.mdpi.com/2072-6694/10/5/140protein-protein interactionYAP-TEAD disruptionmolecular dockingbinding assaysanticancer |
| spellingShingle | 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 Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface Cancers protein-protein interaction YAP-TEAD disruption molecular docking binding assays anticancer |
| title | Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface |
| title_full | Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface |
| title_fullStr | Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface |
| title_full_unstemmed | Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface |
| title_short | Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface |
| title_sort | toward the discovery of a novel class of yap tead interaction inhibitors by virtual screening approach targeting yap tead protein protein interface |
| topic | protein-protein interaction YAP-TEAD disruption molecular docking binding assays anticancer |
| url | http://www.mdpi.com/2072-6694/10/5/140 |
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