Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0178381
Title: Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
Authors: Kaan H.Y.K.
Sim A.Y.L.
Tan S.K.J.
Verma C. 
Song H. 
Keywords: phenylalanine
transcription factor
transcription factor TAZ
transcription factor TEAD
transcription factor YAP
unclassified drug
ligand
protein binding
transcription factor
Article
binding site
cancer therapy
cell proliferation
complex formation
controlled study
genetic transcription
Hippo signaling pathway
human
human cell
protein protein interaction
signal transduction
structure activity relation
X ray crystallography
animal
calorimetry
chemistry
computer simulation
metabolism
mouse
Animals
Calorimetry
Computer Simulation
Crystallography, X-Ray
Humans
Ligands
Mice
Protein Binding
Structure-Activity Relationship
Transcription Factors
Issue Date: 2017
Publisher: Public Library of Science
Citation: Kaan H.Y.K., Sim A.Y.L., Tan S.K.J., Verma C., Song H. (2017). Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches. PLoS ONE 12 (6) : e0178381. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0178381
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/TAZTEAD 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. © 2017 Kaan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/165793
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0178381
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