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Updated: Jul 11, 2025

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A covalent inhibitor of the YAP-TEAD transcriptional complex identified by high-throughput screening

Kayla Nutsch1, Lirui Song2, Emily Chen2

  • 1Department of Chemistry, The Scripps Research Institute La Jolla CA 92037 USA mbollong@scripps.edu.

RSC Chemical Biology
|November 3, 2023
PubMed

Insights

Researchers identified a new drug, mCMY020, that inhibits the Yes-associated protein (YAP) and TEA domain transcription factors (TEADs) interaction. This discovery offers a potential new strategy for cancer therapy by targeting YAP/TEADs in oncology.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Yes-associated protein (YAP) is a key regulator of cell growth and regeneration.
  • Aberrant YAP activation in cancer promotes tumor progression, metastasis, and immune evasion.
  • Targeting YAP, particularly its interaction with TEA domain transcription factors (TEADs), is a promising strategy for cancer therapeutics.

Purpose of the Study:

  • To identify small molecules that inhibit the YAP-TEADs interaction.
  • To develop potent and specific inhibitors for YAP-TEADs transcriptional activity.
  • To explore novel therapeutic approaches for YAP-driven cancers.

Main Methods:

  • High-throughput screening of over 800,000 small molecules using fluorescence polarization.
  • Medicinal chemistry optimization of identified hit compounds.
  • Characterization of inhibitor binding to TEADs.

Main Results:

  • A pyrazolopyrimidine-based scaffold was identified that disrupts YAP-TEADs association.
  • Optimization led to the development of mCMY020, a potent covalent inhibitor of TEADs.
  • mCMY020 targets a conserved palmitoylation site on TEADs, inhibiting their transcriptional activity.

Conclusions:

  • mCMY020 represents a novel, potent inhibitor targeting the YAP-TEADs interaction.
  • This covalent inhibitor offers a promising therapeutic candidate for cancers driven by YAP activation.
  • The findings open new avenues for precision oncology targeting the Hippo-YAP-TEADs pathway.

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