Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex

Disrupting the formation of the oncogenic YAP/TAZ-TEAD transcriptional complex holds substantial therapeutic potential. However, the three protein interaction interfaces of this complex cannot be easily disrupted using small molecules. Here, we report that the pharmacologically active small molecule...

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Bibliographic Details
Published in:PloS one 2022-04, Vol.17 (4), p.e0266143
Main Authors: Che, Kepeng, Pobbati, Ajaybabu V, Seavey, Caleb N, Fedorov, Yuriy, Komar, Anton A, Burtscher, Ashley, Ma, Shuang, Rubin, Brian P
Format: Article
Language:English
Subjects:
Analysis
Assaying
Aurintricarboxylic Acid
Biology
Biology and Life Sciences
Cancer
Cell culture
Chromatography
Disruption
Engineering and Technology
Fluorescence
Fluorescence polarization
Fusion protein
Genetic aspects
Genetic transcription
Interfaces
Medicine and Health Sciences
Mutation
Oncogene Proteins, Fusion
Peptides
Phenotypes
Physical Sciences
Protein expression
Proteins
Research and Analysis Methods
Transcription
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
Tumorigenesis
Verteporfin
Yes-associated protein
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Summary:Disrupting the formation of the oncogenic YAP/TAZ-TEAD transcriptional complex holds substantial therapeutic potential. However, the three protein interaction interfaces of this complex cannot be easily disrupted using small molecules. Here, we report that the pharmacologically active small molecule aurintricarboxylic acid (ATA) acts as a disruptor of the TAZ-TEAD complex. ATA was identified in a high-throughput screen using a TAZ-TEAD AlphaLISA assay that was tailored to identify disruptors of this transcriptional complex. We further used fluorescence polarization assays both to confirm disruption of the TAZ-TEAD complex and to demonstrate that ATA binds to interface 3. We have previously shown that cell-based models that express the oncogenic TAZ-CAMTA1 (TC) fusion protein display enhanced TEAD transcriptional activity because TC functions as an activated form of TAZ. Utilizing cell-based studies and our TC model system, we performed TC/TEAD reporter, RNA-Seq, and qPCR assays and found that ATA inhibits TC/TEAD transcriptional activity. Further, disruption of TC/TEAD and TAZ/TEAD interaction by ATA abrogated anchorage-independent growth, the phenotype most closely linked to dysregulated TAZ/TEAD activity. Therefore, this study demonstrates that ATA is a novel small molecule that has the ability to disrupt the undruggable TAZ-TEAD interface.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0266143