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Fluorescence polarization assay for the identification and evaluation of inhibitors at YAP-TEAD protein-protein

Wei Zhou1, Yiping Li2, Jinhua Song3

  • 1Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, 32610, United States.

Analytical Biochemistry
|September 4, 2019
PubMed

Insights

Researchers developed a new assay to find drugs targeting the YAP-TEAD interaction, crucial for cancer growth. This method successfully identified a small molecule inhibitor, offering a promising avenue for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • The Hippo signaling pathway regulates organ size and cell proliferation.
  • Dysregulation of Hippo signaling, particularly YAP/TAZ activity, is implicated in various cancers.
  • The YAP-TEAD transcriptional complex drives oncogenic gene expression.

Purpose of the Study:

  • To establish a fluorescence polarization (FP)-based assay for identifying inhibitors of the YAP-TEAD protein-protein interaction (PPI).
  • To evaluate inhibitors targeting the YAP Ω-loop binding region on TEAD (interface 3).
  • To validate the utility of the FP assay in drug discovery for cancer treatment.

Main Methods:

  • Development of a fluorescence polarization (FP) assay to measure YAP-TEAD complex formation.
  • Utilizing the FP assay to screen for inhibitors of the YAP-TEAD interaction at interface 3.
  • Characterization of a patented small molecule (Patent-22) as a YAP-TEAD PPI inhibitor using the FP assay.

Main Results:

  • A reliable, robust, and economical FP assay for YAP-TEAD PPI inhibitor assessment was established.
  • The assay successfully identified and evaluated inhibitors targeting interface 3 of the YAP-TEAD binding surface.
  • A patented small molecule, Patent-22, was confirmed as a YAP-TEAD PPI inhibitor at interface 3 via the FP assay.

Conclusions:

  • The developed FP assay is a valuable tool for YAP-TEAD inhibitor discovery and drug development.
  • Targeting the YAP-TEAD PPI offers a novel therapeutic strategy for cancer treatment.
  • The FP assay provides a reliable and economical method for assessing potential cancer therapeutics.
Keywords:
Cyclic peptideDrug discoveryFluorescence polarization (FP)Hippo signaling pathwayK(i)Protein–protein interaction (PPI)Small molecule inhibitorTEADYAPΩ-loop

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