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) , Mathieu Corvaisier (1) , Guillemette Huet (1) , Philippe Chavatte (2) , Patricia Melnyk (1) , Fabrice Bailly (1) , Philippe Cotelle (1)

1 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
2 LIRIC - Lille Inflammation Research International Center - U 995
3 CBS - Centre de Biochimie Structurale [Montpellier]
4 Université de Lille

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.

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

Domaines: Chimie thérapeutique; Chemo-informatique; Cancer

Floriane Gibault, Mathilde Coevoet, Manon Sturbaut, Amaury Farce, Nicolas Renault, et al.. 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 (5), pp.140. ⟨10.3390/cancers10050140⟩. ⟨hal-02060686⟩