The First Class of Small Molecules Potently Disrupting the YAP‐TEAD Interaction by Direct Competition. (2nd September 2022)

• Record Type: Journal Article
• Authors: Furet, Pascal; Bordas, Vincent; Le Douget, Mickaël; Salem, Bahaa; Mesrouze, Yannick; Imbach‐Weese, Patricia; Sellner, Holger; Voegtle, Markus; Soldermann, Nicolas; Chapeau, Emilie; Wartmann, Markus; Scheufler, Clemens; Fernandez, Cesar; Kallen, Joerg; Guagnano, Vito; Chène, Patrick; Schmelzle, Tobias
• Is Part Of: ChemMedChem. Volume 17:Number 19(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-02
• Subjects: TEAD -- YAP -- PPI inhibitors virtual screening -- structure-based design; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200303
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Inhibition of the YAP‐TEAD protein‐protein interaction is an attractive therapeutic concept under intense investigation with the objective to treat cancers associated with a dysregulation of the Hippo pathway. However, owing to the very extended surface of interaction of the two proteins, the identification of small drug‐like molecules able to efficiently prevent YAP from binding to TEAD by direct competition has been elusive so far. We disclose here the discovery of the first class of small molecules potently inhibiting the YAP‐TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD. These inhibitors, providing a path forward to pharmacological intervention in the Hippo pathway, evolved from a weakly active virtual screening hit advanced to high potency by structure‐based design. Abstract : Inhibiting protein‐protein interactions with small drug‐like molecules is extremely challenging. We report here a breakthrough regarding the YAP‐TEAD interaction. The potency of a weakly active virtual screening hit was increased by five orders of magnitude by structure‐based design, providing the first class of small molecules able to efficiently disrupt the YAP‐TEAD interaction, an important target in oncology.