Journal
CHEMMEDCHEM
Volume 16, Issue 18, Pages 2823-2844Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100153
Keywords
antitumor agents; Hippo pathway; protein-protein interaction; TEAD binding; YAP-TEAD inhibition
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Funding
- le Ministere de l'Education et de la Recherche
- le Canceropole Nord-Ouest [2016/09]
- Region Nord Pas-de-Calais (France)
- Ministere de la Jeunesse, de l'Education Nationale et de la Recherche (MJENR)
- Fonds Europeens de Developpement Regional (FEDER)
- SIRIC OncoLille
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Synthesized compounds were found to inhibit the activity of the YAP/TAZ-TEAD complex, with some displaying cytotoxic effects on cells. Despite this, they serve as promising starting points for the development of effective YAP-TEAD disruptors in the future.
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.
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