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Discovery of a selective inhibitor of Doublecortin Like Kinase 1
Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We leveraged chemoproteomic profiling and structure-based design to de...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
2020
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246176/ https://www.ncbi.nlm.nih.gov/pubmed/32251410 http://dx.doi.org/10.1038/s41589-020-0506-0 |
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| author | Ferguson, Fleur M. Nabet, Behnam Raghavan, Srivatsan Liu, Yan Leggett, Alan L. Kuljanin, Miljan Kalekar, Radha L. Yang, Annan He, Shuning Wang, Jinhua Ng, Raymond W. S. Sulahian, Rita Li, Lianbo Poulin, Emily J. Huang, Ling Koren, Jost Dieguez-Martinez, Nora Espinosa, Sergio Zeng, Zhiyang Corona, Cesear R. Vasta, James D. Ohi, Ryoma Sim, Taebo Kim, Nam Doo Harshbarger, Wayne Lizcano, Jose M. Robers, Matthew B. Muthaswamy, Senthil Lin, Charles Y. Look, A. Thomas Haigis, Kevin M. Mancias, Joseph D. Wolpin, Brian M. Aguirre, Andrew J. Hahn, William C. Westover, Kenneth D. Gray, Nathanael S. |
| author_facet | Ferguson, Fleur M. Nabet, Behnam Raghavan, Srivatsan Liu, Yan Leggett, Alan L. Kuljanin, Miljan Kalekar, Radha L. Yang, Annan He, Shuning Wang, Jinhua Ng, Raymond W. S. Sulahian, Rita Li, Lianbo Poulin, Emily J. Huang, Ling Koren, Jost Dieguez-Martinez, Nora Espinosa, Sergio Zeng, Zhiyang Corona, Cesear R. Vasta, James D. Ohi, Ryoma Sim, Taebo Kim, Nam Doo Harshbarger, Wayne Lizcano, Jose M. Robers, Matthew B. Muthaswamy, Senthil Lin, Charles Y. Look, A. Thomas Haigis, Kevin M. Mancias, Joseph D. Wolpin, Brian M. Aguirre, Andrew J. Hahn, William C. Westover, Kenneth D. Gray, Nathanael S. |
| author_sort | Ferguson, Fleur M. |
| collection | PubMed |
| description | Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We leveraged chemoproteomic profiling and structure-based design to develop the first selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC organoid models and use a combination of RNA sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in cancer. |
| format | Online Article Text |
| id | pubmed-7246176 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2020 |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-72461762020-10-06 Discovery of a selective inhibitor of Doublecortin Like Kinase 1 Ferguson, Fleur M. Nabet, Behnam Raghavan, Srivatsan Liu, Yan Leggett, Alan L. Kuljanin, Miljan Kalekar, Radha L. Yang, Annan He, Shuning Wang, Jinhua Ng, Raymond W. S. Sulahian, Rita Li, Lianbo Poulin, Emily J. Huang, Ling Koren, Jost Dieguez-Martinez, Nora Espinosa, Sergio Zeng, Zhiyang Corona, Cesear R. Vasta, James D. Ohi, Ryoma Sim, Taebo Kim, Nam Doo Harshbarger, Wayne Lizcano, Jose M. Robers, Matthew B. Muthaswamy, Senthil Lin, Charles Y. Look, A. Thomas Haigis, Kevin M. Mancias, Joseph D. Wolpin, Brian M. Aguirre, Andrew J. Hahn, William C. Westover, Kenneth D. Gray, Nathanael S. Nat Chem Biol Article Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We leveraged chemoproteomic profiling and structure-based design to develop the first selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC organoid models and use a combination of RNA sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in cancer. 2020-04-06 2020-06 /pmc/articles/PMC7246176/ /pubmed/32251410 http://dx.doi.org/10.1038/s41589-020-0506-0 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
| spellingShingle | Article Ferguson, Fleur M. Nabet, Behnam Raghavan, Srivatsan Liu, Yan Leggett, Alan L. Kuljanin, Miljan Kalekar, Radha L. Yang, Annan He, Shuning Wang, Jinhua Ng, Raymond W. S. Sulahian, Rita Li, Lianbo Poulin, Emily J. Huang, Ling Koren, Jost Dieguez-Martinez, Nora Espinosa, Sergio Zeng, Zhiyang Corona, Cesear R. Vasta, James D. Ohi, Ryoma Sim, Taebo Kim, Nam Doo Harshbarger, Wayne Lizcano, Jose M. Robers, Matthew B. Muthaswamy, Senthil Lin, Charles Y. Look, A. Thomas Haigis, Kevin M. Mancias, Joseph D. Wolpin, Brian M. Aguirre, Andrew J. Hahn, William C. Westover, Kenneth D. Gray, Nathanael S. Discovery of a selective inhibitor of Doublecortin Like Kinase 1 |
| title | Discovery of a selective inhibitor of Doublecortin Like Kinase 1 |
| title_full | Discovery of a selective inhibitor of Doublecortin Like Kinase 1 |
| title_fullStr | Discovery of a selective inhibitor of Doublecortin Like Kinase 1 |
| title_full_unstemmed | Discovery of a selective inhibitor of Doublecortin Like Kinase 1 |
| title_short | Discovery of a selective inhibitor of Doublecortin Like Kinase 1 |
| title_sort | discovery of a selective inhibitor of doublecortin like kinase 1 |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246176/ https://www.ncbi.nlm.nih.gov/pubmed/32251410 http://dx.doi.org/10.1038/s41589-020-0506-0 |
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