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
| Autor: | Ajaybabu V. Pobbati, Martine Pugnière, Ashley Burtscher, Patricia Melnyk, Fabrice Bailly, Brian P. Rubin, Frédéric Allemand, Manon Sturbaut, Philippe Cotelle, Jean-François Guichou, Floriane Gibault, Wanjin Hong, Mathilde Coevoet |
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| Rok vydání: | 2021 |
| Předmět: |
1
2 3-Triazole Cell Survival Antineoplastic Agents Biochemistry Fluorescence spectroscopy Protein–protein interaction Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Cytotoxic T cell General Pharmacology Toxicology and Pharmaceutics Cells Cultured Cell Proliferation Pharmacology Reporter gene Hippo signaling pathway Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry HEK 293 cells Hydrazones TEA Domain Transcription Factors YAP-Signaling Proteins Triazoles HEK293 Cells Drug Design Transcriptional Coactivator with PDZ-Binding Motif Proteins Molecular Medicine Drug Screening Assays Antitumor Fluorescence anisotropy |
| Zdroj: | ChemMedChem. 16:2823-2844 |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.202100153 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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