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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 |
Appears in Collections: | Staff Publications Elements |
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