The First Class of Small Molecules Potently Disrupting the YAP-TEAD Interaction by Direct Competition

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The YAP-TEAD protein-protein interaction is a key target for treating cancers involving Hippo pathway dysregulation.
• Directly inhibiting this interaction with small molecules has been challenging due to the large interaction surface.
• Existing therapeutic strategies face limitations in effectively blocking YAP from binding to TEAD.

Purpose of the Study:

• To discover and develop potent small molecule inhibitors of the YAP-TEAD protein-protein interaction.
• To identify novel compounds capable of blocking YAP binding to TEAD at a primary interaction site.
• To establish a foundation for pharmacological intervention in the Hippo pathway for cancer treatment.

Main Methods:

• Utilized virtual screening to identify initial hit compounds.
• Employed structure-based drug design to optimize lead compounds.
• Focused on molecules binding to a specific interaction site on TEAD, occupied by YAP.

Main Results:

• Discovered the first class of potent small molecules inhibiting the YAP-TEAD interaction.
• Identified inhibitors that bind to a critical YAP interaction site on the TEAD protein.
• Successfully advanced a weakly active virtual screening hit to high potency through structure-based design.

Conclusions:

• These novel inhibitors represent a significant advancement in targeting the YAP-TEAD interaction.
• The findings provide a promising path toward pharmacological intervention in the Hippo pathway for cancer therapy.
• Structure-based design was crucial in overcoming the challenges of inhibiting this protein-protein interaction.