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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78810 |
| _version_ | 1828122922727768064 |
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| author | Mengyang Fan Wenchao Lu Jianwei Che Nicholas P Kwiatkowski Yang Gao Hyuk-Soo Seo Scott B Ficarro Prafulla C Gokhale Yao Liu Ezekiel A Geffken Jimit Lakhani Kijun Song Miljan Kuljanin Wenzhi Ji Jie Jiang Zhixiang He Jason Tse Andrew S Boghossian Matthew G Rees Melissa M Ronan Jennifer A Roth Joseph D Mancias Jarrod A Marto Sirano Dhe-Paganon Tinghu Zhang Nathanael S Gray |
| author_facet | Mengyang Fan Wenchao Lu Jianwei Che Nicholas P Kwiatkowski Yang Gao Hyuk-Soo Seo Scott B Ficarro Prafulla C Gokhale Yao Liu Ezekiel A Geffken Jimit Lakhani Kijun Song Miljan Kuljanin Wenzhi Ji Jie Jiang Zhixiang He Jason Tse Andrew S Boghossian Matthew G Rees Melissa M Ronan Jennifer A Roth Joseph D Mancias Jarrod A Marto Sirano Dhe-Paganon Tinghu Zhang Nathanael S Gray |
| author_sort | Mengyang Fan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T14:44:09Z |
| format | Article |
| id | doaj.art-885c81e0f1964e4e986cf2271d9a8b62 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T14:44:09Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-885c81e0f1964e4e986cf2271d9a8b622022-12-22T04:17:45ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.78810Covalent disruptor of YAP-TEAD association suppresses defective Hippo signalingMengyang Fan0https://orcid.org/0000-0002-0871-8792Wenchao Lu1https://orcid.org/0000-0003-1175-365XJianwei Che2Nicholas P Kwiatkowski3Yang Gao4Hyuk-Soo Seo5Scott B Ficarro6Prafulla C Gokhale7Yao Liu8Ezekiel A Geffken9Jimit Lakhani10Kijun Song11https://orcid.org/0000-0002-6037-9345Miljan Kuljanin12Wenzhi Ji13Jie Jiang14https://orcid.org/0000-0003-3795-672XZhixiang He15Jason Tse16Andrew S Boghossian17https://orcid.org/0000-0002-7008-8138Matthew G Rees18Melissa M Ronan19Jennifer A Roth20Joseph D Mancias21Jarrod A Marto22Sirano Dhe-Paganon23Tinghu Zhang24https://orcid.org/0000-0003-1028-8020Nathanael S Gray25https://orcid.org/0000-0001-5354-7403Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, ChinaDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States; Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United StatesExperimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United StatesDepartment of Cell Biology, Harvard Medical School, Boston, United States; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana- Farber Cancer Institute, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States; Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, United StatesBroad Institute of MIT and Harvard, Cambridge, United StatesBroad Institute of MIT and Harvard, Cambridge, United StatesBroad Institute of MIT and Harvard, Cambridge, United StatesBroad Institute of MIT and Harvard, Cambridge, United StatesDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana- Farber Cancer Institute, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States; Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States; Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, United StatesThe 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.https://elifesciences.org/articles/78810YAPTEADpalmitoylationcovalent ligandtranscription factorsmesothelioma |
| spellingShingle | Mengyang Fan Wenchao Lu Jianwei Che Nicholas P Kwiatkowski Yang Gao Hyuk-Soo Seo Scott B Ficarro Prafulla C Gokhale Yao Liu Ezekiel A Geffken Jimit Lakhani Kijun Song Miljan Kuljanin Wenzhi Ji Jie Jiang Zhixiang He Jason Tse Andrew S Boghossian Matthew G Rees Melissa M Ronan Jennifer A Roth Joseph D Mancias Jarrod A Marto Sirano Dhe-Paganon Tinghu Zhang Nathanael S Gray Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling eLife YAP TEAD palmitoylation covalent ligand transcription factors mesothelioma |
| 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 | YAP TEAD palmitoylation covalent ligand transcription factors mesothelioma |
| url | https://elifesciences.org/articles/78810 |
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