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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
Hung Yi Kristal Kaan1, Adelene Y L Sim2, Siew Kim Joyce Tan1
1Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Singapore.
Abstract:
The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site.
Insights
Researchers identified a key fragment that disrupts the YAP/TAZ-TEAD complex, a crucial target in cancer therapy. This discovery provides a scaffold for developing new drugs to inhibit cell proliferation and treat cancer.
Area of Science:
- Molecular Biology
- Biochemistry
- Oncology
Background:
- The Hippo signaling pathway regulates organ size and is a promising target for cancer therapeutics.
- YAP, TAZ, and TEAD form a complex that drives transcription of growth-promoting genes, crucial for cell proliferation.
- Disrupting the YAP/TAZ-TEAD complex can inhibit cancer cell growth.
Purpose of the Study:
- To identify small molecules that can disrupt the YAP/TAZ-TEAD protein-protein interactions.
- To establish a validated druggable binding site for therapeutic intervention.
- To develop a scaffold for novel cancer therapeutics targeting the Hippo pathway.
Main Methods:
- Screening of a 1000-member fragment library using Thermal Shift Assay (TSA).
- X-ray crystallography to confirm binding and determine the binding mode of the hit fragment.
- Structure-activity relationship (SAR) studies and computational modeling.
Main Results:
- A hit fragment was identified that binds to the YAP/TAZ-TEAD interface.
- The fragment occupies a hydrophobic pocket, similar to a conserved phenylalanine in YAP/TAZ.
- The identified fragment serves as a promising scaffold for developing YAP/TAZ-TEAD inhibitors.
Conclusions:
- The YAP/TAZ-TEAD interaction site is a validated druggable target for cancer therapy.
- The identified fragment is a valuable starting point for designing potent inhibitors of YAP/TAZ-TEAD complex formation.
- This work lays the foundation for developing novel anti-cancer drugs targeting the Hippo signaling pathway.
