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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007350/?tool=EBI |
| _version_ | 1811332032805994496 |
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| author | Kepeng Che Ajaybabu V. Pobbati Caleb N. Seavey Yuriy Fedorov Anton A. Komar Ashley Burtscher Shuang Ma Brian P. Rubin |
| author_facet | Kepeng Che Ajaybabu V. Pobbati Caleb N. Seavey Yuriy Fedorov Anton A. Komar Ashley Burtscher Shuang Ma Brian P. Rubin |
| author_sort | Kepeng Che |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T16:29:42Z |
| format | Article |
| id | doaj.art-7f54053962634a159d61043de6ba9725 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T16:29:42Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7f54053962634a159d61043de6ba97252022-12-22T02:39:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-01174Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complexKepeng CheAjaybabu V. PobbatiCaleb N. SeaveyYuriy FedorovAnton A. KomarAshley BurtscherShuang MaBrian P. RubinDisrupting 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.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007350/?tool=EBI |
| spellingShingle | Kepeng Che Ajaybabu V. Pobbati Caleb N. Seavey Yuriy Fedorov Anton A. Komar Ashley Burtscher Shuang Ma Brian P. Rubin Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex PLoS ONE |
| title | Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex |
| title_full | Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex |
| title_fullStr | Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex |
| title_full_unstemmed | Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex |
| title_short | Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex |
| title_sort | aurintricarboxylic acid is a canonical disruptor of the taz tead transcriptional complex |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007350/?tool=EBI |
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