Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors
Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit th...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/129478 |
| _version_ | 1826198108407595008 |
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| author | Tan, Li Gurbani, Deepak Weisberg, Ellen L. Jones II, Douglas S. Rao, Suman Singer, William D. Bernard, Faviola M. Mowafy, Samar Jenney, Annie Du, Guangyan Nonami, Atsushi Griffin, James D. Lauffenburger, Douglas A Westover, Kenneth D. Sorger, Peter K. Gray, Nathanael S. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Tan, Li Gurbani, Deepak Weisberg, Ellen L. Jones II, Douglas S. Rao, Suman Singer, William D. Bernard, Faviola M. Mowafy, Samar Jenney, Annie Du, Guangyan Nonami, Atsushi Griffin, James D. Lauffenburger, Douglas A Westover, Kenneth D. Sorger, Peter K. Gray, Nathanael S. |
| author_sort | Tan, Li |
| collection | MIT |
| description | Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases. |
| first_indexed | 2024-09-23T10:59:27Z |
| format | Article |
| id | mit-1721.1/129478 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:59:27Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1294782022-09-27T16:22:39Z Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors Tan, Li Gurbani, Deepak Weisberg, Ellen L. Jones II, Douglas S. Rao, Suman Singer, William D. Bernard, Faviola M. Mowafy, Samar Jenney, Annie Du, Guangyan Nonami, Atsushi Griffin, James D. Lauffenburger, Douglas A Westover, Kenneth D. Sorger, Peter K. Gray, Nathanael S. Massachusetts Institute of Technology. Department of Biological Engineering Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases. 2021-01-20T19:18:47Z 2021-01-20T19:18:47Z 2017-02 2016-11 2019-09-23T11:19:20Z Article http://purl.org/eprint/type/JournalArticle 0968-0896 https://hdl.handle.net/1721.1/129478 Tan, Li et al. "Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors." Bioorganic & Medicinal Chemistry 25, 4 (Febraury 2017): 1320-1328. © 2016 Elsevier Ltd en http://dx.doi.org/10.1016/j.bmc.2016.11.034 Bioorganic & Medicinal Chemistry Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Tan, Li Gurbani, Deepak Weisberg, Ellen L. Jones II, Douglas S. Rao, Suman Singer, William D. Bernard, Faviola M. Mowafy, Samar Jenney, Annie Du, Guangyan Nonami, Atsushi Griffin, James D. Lauffenburger, Douglas A Westover, Kenneth D. Sorger, Peter K. Gray, Nathanael S. Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors |
| title | Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors |
| title_full | Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors |
| title_fullStr | Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors |
| title_full_unstemmed | Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors |
| title_short | Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors |
| title_sort | studies of tak1 centered polypharmacology with novel covalent tak1 inhibitors |
| url | https://hdl.handle.net/1721.1/129478 |
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