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

Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
Title:
Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
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PLOS One
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Publication Date:
01 June 2017
Citation:
Article Source: Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches Kaan HYK, Sim AYL, Tan SKJ, Verma C, Song H (2017) Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches. PLOS ONE 12(6): e0178381. 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/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.
License type:
http://creativecommons.org/licenses/by-nd/4.0/
Funding Info:
This work is financially supported by the 2013 BMRC Young Investigator Grant (No.: 1310151003) awarded by the Agency for Science, Technology, and Research in Singapore to HYKK, and NMRC Open Fund Individual Research (OF-IRG) Grant (No: NMRC/OFIRG/0024/2016) in Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Description:
ISSN:
932-6203
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