Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors.
PPI inhibitors
TEAD
YAP
in vivo efficacy
multi-parameter optimization
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
01 06 2023
01 06 2023
Historique:
revised:
15
03
2023
received:
01
02
2023
medline:
5
6
2023
pubmed:
30
3
2023
entrez:
29
3
2023
Statut:
ppublish
Résumé
The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.
Identifiants
pubmed: 36988034
doi: 10.1002/cmdc.202300051
doi:
Substances chimiques
Transcription Factors
0
YAP-Signaling Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300051Informations de copyright
© 2023 Wiley-VCH GmbH.
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