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Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728995/ https://www.ncbi.nlm.nih.gov/pubmed/36300789 http://dx.doi.org/10.7554/eLife.78810 |
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author | Fan, Mengyang Lu, Wenchao Che, Jianwei Kwiatkowski, Nicholas P Gao, Yang Seo, Hyuk-Soo Ficarro, Scott B Gokhale, Prafulla C Liu, Yao Geffken, Ezekiel A Lakhani, Jimit Song, Kijun Kuljanin, Miljan Ji, Wenzhi Jiang, Jie He, Zhixiang Tse, Jason Boghossian, Andrew S Rees, Matthew G Ronan, Melissa M Roth, Jennifer A Mancias, Joseph D Marto, Jarrod A Dhe-Paganon, Sirano Zhang, Tinghu Gray, Nathanael S |
author_facet | Fan, Mengyang Lu, Wenchao Che, Jianwei Kwiatkowski, Nicholas P Gao, Yang Seo, Hyuk-Soo Ficarro, Scott B Gokhale, Prafulla C Liu, Yao Geffken, Ezekiel A Lakhani, Jimit Song, Kijun Kuljanin, Miljan Ji, Wenzhi Jiang, Jie He, Zhixiang Tse, Jason Boghossian, Andrew S Rees, Matthew G Ronan, Melissa M Roth, Jennifer A Mancias, Joseph D Marto, Jarrod A Dhe-Paganon, Sirano Zhang, Tinghu Gray, Nathanael S |
author_sort | Fan, Mengyang |
collection | PubMed |
description | The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration. |
format | Online Article Text |
id | pubmed-9728995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-97289952022-12-08 Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling Fan, Mengyang Lu, Wenchao Che, Jianwei Kwiatkowski, Nicholas P Gao, Yang Seo, Hyuk-Soo Ficarro, Scott B Gokhale, Prafulla C Liu, Yao Geffken, Ezekiel A Lakhani, Jimit Song, Kijun Kuljanin, Miljan Ji, Wenzhi Jiang, Jie He, Zhixiang Tse, Jason Boghossian, Andrew S Rees, Matthew G Ronan, Melissa M Roth, Jennifer A Mancias, Joseph D Marto, Jarrod A Dhe-Paganon, Sirano Zhang, Tinghu Gray, Nathanael S eLife Biochemistry and Chemical Biology The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration. eLife Sciences Publications, Ltd 2022-10-27 /pmc/articles/PMC9728995/ /pubmed/36300789 http://dx.doi.org/10.7554/eLife.78810 Text en © 2022, Fan, Lu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Fan, Mengyang Lu, Wenchao Che, Jianwei Kwiatkowski, Nicholas P Gao, Yang Seo, Hyuk-Soo Ficarro, Scott B Gokhale, Prafulla C Liu, Yao Geffken, Ezekiel A Lakhani, Jimit Song, Kijun Kuljanin, Miljan Ji, Wenzhi Jiang, Jie He, Zhixiang Tse, Jason Boghossian, Andrew S Rees, Matthew G Ronan, Melissa M Roth, Jennifer A Mancias, Joseph D Marto, Jarrod A Dhe-Paganon, Sirano Zhang, Tinghu Gray, Nathanael S Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling |
title | Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling |
title_full | Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling |
title_fullStr | Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling |
title_full_unstemmed | Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling |
title_short | Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling |
title_sort | covalent disruptor of yap-tead association suppresses defective hippo signaling |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728995/ https://www.ncbi.nlm.nih.gov/pubmed/36300789 http://dx.doi.org/10.7554/eLife.78810 |
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