The First Class of Small Molecules Potently Disrupting the YAP-TEAD Interaction by Direct Competition.
PPI inhibitors •virtual screening
TEAD
YAP
structure-based design
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
06 10 2022
06 10 2022
Historique:
revised:
10
08
2022
received:
01
06
2022
pubmed:
12
8
2022
medline:
12
10
2022
entrez:
11
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35950546
doi: 10.1002/cmdc.202200303
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Transcription Factors
0
YAP-Signaling Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202200303Informations de copyright
© 2022 Wiley-VCH GmbH.
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