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

ChemMedChem. 2021 Sep 16;16(18):2823-2844. doi: 10.1002/cmdc.202100153. Epub 2021 Jul 1.

Abstract

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.

Keywords: Hippo pathway; TEAD binding; YAP-TEAD inhibition; antitumor agents; protein-protein interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • 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
  • Hydrazones / chemistry
  • Hydrazones / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship
  • TEA Domain Transcription Factors / antagonists & inhibitors*
  • TEA Domain Transcription Factors / metabolism
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / antagonists & inhibitors*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / metabolism
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • YAP-Signaling Proteins / antagonists & inhibitors*
  • YAP-Signaling Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Hydrazones
  • TEA Domain Transcription Factors
  • TEAD2 protein, human
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Triazoles
  • YAP-Signaling Proteins
  • YAP1 protein, human