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

• Main Authors: Kaan, Hung Yi Kristal, Sim, Adelene Y. L., Tan, Siew Kim Joyce, Verma, Chandra, Song, Haiwei
• Other Authors: Ye, Sheng
• Format: Article
• Language: English
• Published: 2018
• Subjects: Phenylalanine; Transcription Factor TAZ
• Online Access: https://hdl.handle.net/10356/88193; http://hdl.handle.net/10220/44583
• Institution: Nanyang Technological University

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.