Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches

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.