Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
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 pat...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2018
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| Online Access: | https://hdl.handle.net/10356/88193 http://hdl.handle.net/10220/44583 |
| _version_ | 1811686847138496512 |
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| author | Kaan, Hung Yi Kristal Sim, Adelene Y. L. Tan, Siew Kim Joyce Verma, Chandra Song, Haiwei |
| author2 | Ye, Sheng |
| author_facet | Ye, Sheng Kaan, Hung Yi Kristal Sim, Adelene Y. L. Tan, Siew Kim Joyce Verma, Chandra Song, Haiwei |
| author_sort | Kaan, Hung Yi Kristal |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:06:55Z |
| format | Journal Article |
| id | ntu-10356/88193 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:06:55Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/881932023-02-28T17:01:55Z Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches Kaan, Hung Yi Kristal Sim, Adelene Y. L. Tan, Siew Kim Joyce Verma, Chandra Song, Haiwei Ye, Sheng School of Biological Sciences Phenylalanine Transcription Factor TAZ 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version 2018-03-19T04:57:03Z 2019-12-06T16:58:07Z 2018-03-19T04:57:03Z 2019-12-06T16:58:07Z 2017 Journal Article 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-. https://hdl.handle.net/10356/88193 http://hdl.handle.net/10220/44583 10.1371/journal.pone.0178381 en PLOS ONE © 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. 18 p. application/pdf |
| spellingShingle | Phenylalanine Transcription Factor TAZ Kaan, Hung Yi Kristal Sim, Adelene Y. L. Tan, Siew Kim Joyce Verma, Chandra Song, Haiwei 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 |
| title_full | Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches |
| title_fullStr | Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches |
| title_full_unstemmed | Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches |
| title_short | Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches |
| title_sort | targeting yap taz tead protein protein interactions using fragment based and computational modeling approaches |
| topic | Phenylalanine Transcription Factor TAZ |
| url | https://hdl.handle.net/10356/88193 http://hdl.handle.net/10220/44583 |
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