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TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway.

Alissa D Guarnaccia1,2, Thijs J Hagenbeek2, Wendy Lee3

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Proceedings of the National Academy of Sciences of the United States of America
|July 3, 2025
PubMed
Summary

New TEAD inhibitors act as "molecular glues," promoting the repressive VGLL4-TEAD interaction. This approach counters oncogenic Hippo pathway activity by outcompeting YAP-TEAD complexes, offering a novel cancer therapy strategy.

Keywords:
HippoTEADVGLL4cancer therapymolecular glue

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • TEAD proteins are key in Hippo pathway signaling and cancer.
  • Current drugs target TEAD-YAP/TAZ interactions.
  • An alternative mechanism for TEAD inhibition is explored.

Purpose of the Study:

  • To investigate a novel mechanism of TEAD inhibition by sulfonamide compounds.
  • To identify compounds that modulate TEAD cofactor interactions.
  • To explore the role of VGLL4 in TEAD-mediated transcriptional regulation.

Main Methods:

  • Screening of TEAD-targeting compounds.
  • Biochemical assays to detect TEAD-cofactor interactions.
  • Cell-based proliferation assays.
  • Gene expression analysis.
  • In vivo studies in mouse models.

Main Results:

  • Select sulfonamide compounds enhance TEAD interaction with the repressor VGLL4.
  • This VGLL4-TEAD complex formation inhibits proliferation by displacing YAP-TEAD.
  • VGLL4 is essential for the antiproliferative effects of these compounds.
  • Overexpression of VGLL4 sensitizes cells to these compounds, while deletion abolishes sensitivity.

Conclusions:

  • A new class of TEAD inhibitors functions as "molecular glues" promoting VGLL4-TEAD interaction.
  • This mechanism offers a novel strategy to counteract oncogenic Hippo pathway signaling.
  • These findings advance understanding of TEAD-targeted cancer therapies.