Design, Synthesis and Evaluation of a Series of 1,5-Diaryl-1,2,3-triazole-4-carbohydrazones as Inhibitors of the YAP-TAZ/TEAD Complex.
Antineoplastic Agents
/ chemical synthesis
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
HEK293 Cells
Humans
Hydrazones
/ chemical synthesis
Molecular Structure
Structure-Activity Relationship
TEA Domain Transcription Factors
/ antagonists & inhibitors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
/ antagonists & inhibitors
Triazoles
/ chemical synthesis
YAP-Signaling Proteins
/ antagonists & inhibitors
Hippo pathway
TEAD binding
YAP-TEAD inhibition
antitumor agents
protein-protein interaction
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
16 09 2021
16 09 2021
Historique:
received:
03
03
2021
pubmed:
26
5
2021
medline:
17
2
2022
entrez:
25
5
2021
Statut:
ppublish
Résumé
Starting from our previously reported hit, a series of 1,5-diaryl-1,2,3-triazole-4-carbohydrazones were synthesized and evaluated as inhibitors of the YAP/TAZ-TEAD complex. Their binding to hTEAD2 was confirmed by nanodifferential scanning fluorimetry, and some of the compounds were also found to moderately disrupt the YAP-TEAD interaction, as assessed by a fluorescence polarization assay. A TEAD luciferase gene reporter assay performed in HEK293T cells and RTqPCR measurements in MDA-MB231 cells showed that these compounds inhibit YAP/TAZ-TEAD activity to cells in the micromolar range. In spite of the cytotoxic effects displayed by some of the compounds of this series, they are still good starting points and can be suitably modified into an effective and viable YAP-TEAD disruptor in the future.
Identifiants
pubmed: 34032019
doi: 10.1002/cmdc.202100153
doi:
Substances chimiques
Antineoplastic Agents
0
Hydrazones
0
TEA Domain Transcription Factors
0
TEAD2 protein, human
0
Transcriptional Coactivator with PDZ-Binding Motif Proteins
0
Triazoles
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2823-2844Subventions
Organisme : le Ministère de l'Education et de la Recherche
Organisme : SIRIC OncoLille and le Cancéropôle Nord-Ouest
ID : 2016/09
Organisme : Région Nord Pas-de-Calais
Organisme : Ministère de la Jeunesse, de l'Education Nationale et de la Recherche
Organisme : Fonds Européens de Développement Régional
Informations de copyright
© 2021 Wiley-VCH GmbH.
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