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Title: Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
Authors: Kaan, Hung Yi Kristal
Sim, Adelene Y. L.
Tan, Siew Kim Joyce
Verma, Chandra
Song, Haiwei
Keywords: Phenylalanine
Transcription Factor TAZ
Issue Date: 2017
Source: 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-.
Series/Report no.: PLOS ONE
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/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.
DOI: 10.1371/journal.pone.0178381
Rights: © 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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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