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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
Author(s) -
Gibault Floriane,
Sturbaut Ma,
Coevoet Mathilde,
Pugnière Martine,
Burtscher Ashley,
Allemand Frédéric,
Melnyk Patricia,
Hong Wanjin,
Rubin Brian P.,
Pobbati Ajaybabu V.,
Guichou JeanFrançois,
Cotelle Philippe,
Bailly Fabrice
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100153
Subject(s) - triazole , chemistry , luciferase , hek 293 cells , reporter gene , fluorescence , cytotoxic t cell , stereochemistry , in vitro , combinatorial chemistry , biochemistry , gene , transfection , gene expression , physics , organic chemistry , quantum mechanics
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.