Discovery of a selective inhibitor of doublecortin like kinase 1

Fleur M. Ferguson; Behnam Nabet; Srivatsan Raghavan; Yan Liu; Alan L. Leggett; Miljan Kuljanin; Radha L. Kalekar; Annan Yang; Shuning He; Jinhua Wang; Raymond W.S. Ng; Rita Sulahian; Lianbo Li; Emily J. Poulin; Ling Huang; Jost Koren; Nora Dieguez-Martinez; Sergio Espinosa; Zhiyang Zeng; Cesear R. Corona; James D. Vasta; Ryoma Ohi; Taebo Sim; Nam Doo Kim; Wayne Harshbarger; Jose M. Lizcano; Matthew B. Robers; Senthil Muthaswamy; Charles Y. Lin; A. Thomas Look; Kevin M. Haigis; Joseph D. Mancias; Brian M. Wolpin; Andrew J. Aguirre; William C. Hahn; Kenneth D. Westover; Nathanael S. Gray

doi:10.1038/s41589-020-0506-0

Discovery of a selective inhibitor of doublecortin like kinase 1

Fleur M. Ferguson, Behnam Nabet, Srivatsan Raghavan, Yan Liu, Alan L. Leggett, Miljan Kuljanin, Radha L. Kalekar, Annan Yang, Shuning He, Jinhua Wang, Raymond W.S. Ng, Rita Sulahian, Lianbo Li, Emily J. Poulin, Ling Huang, Jost Koren, Nora Dieguez-Martinez, Sergio Espinosa, Zhiyang Zeng, Cesear R. CoronaJames D. Vasta, Ryoma Ohi, Taebo Sim, Nam Doo Kim, Wayne Harshbarger, Jose M. Lizcano, Matthew B. Robers, Senthil Muthaswamy, Charles Y. Lin, A. Thomas Look, Kevin M. Haigis, Joseph D. Mancias, Brian M. Wolpin, Andrew J. Aguirre, William C. Hahn, Kenneth D. Westover, Nathanael S. Gray

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74 Scopus citations

Abstract

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 used chemoproteomic profiling and structure-based design to develop a 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. [Figure not available: see fulltext.].

Original language	English (US)
Pages (from-to)	635-643
Number of pages	9
Journal	Nature chemical biology
Volume	16
Issue number	6
DOIs	https://doi.org/10.1038/s41589-020-0506-0
State	Published - Jun 1 2020

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Ferguson, F. M., Nabet, B., Raghavan, S., Liu, Y., Leggett, A. L., Kuljanin, M., Kalekar, R. L., Yang, A., He, S., Wang, J., Ng, R. W. S., Sulahian, R., Li, L., Poulin, E. J., Huang, L., Koren, J., Dieguez-Martinez, N., Espinosa, S., Zeng, Z., ... Gray, N. S. (2020). Discovery of a selective inhibitor of doublecortin like kinase 1. Nature chemical biology, 16(6), 635-643. https://doi.org/10.1038/s41589-020-0506-0

Ferguson, FM, Nabet, B, Raghavan, S, Liu, Y, Leggett, AL, Kuljanin, M, Kalekar, RL, Yang, A, He, S, Wang, J, Ng, RWS, Sulahian, R, Li, L, Poulin, EJ, Huang, L, Koren, J, Dieguez-Martinez, N, Espinosa, S, Zeng, Z, Corona, CR, Vasta, JD, Ohi, R, Sim, T, Kim, ND, Harshbarger, W, Lizcano, JM, Robers, MB, Muthaswamy, S, Lin, CY, Look, AT, Haigis, KM, Mancias, JD, Wolpin, BM, Aguirre, AJ, Hahn, WC, Westover, KD & Gray, NS 2020, 'Discovery of a selective inhibitor of doublecortin like kinase 1', Nature chemical biology, vol. 16, no. 6, pp. 635-643. https://doi.org/10.1038/s41589-020-0506-0

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title = "Discovery of a selective inhibitor of doublecortin like kinase 1",

abstract = "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 used chemoproteomic profiling and structure-based design to develop a 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. [Figure not available: see fulltext.].",

author = "Ferguson, {Fleur M.} and Behnam Nabet and Srivatsan Raghavan and Yan Liu and Leggett, {Alan L.} and Miljan Kuljanin and Kalekar, {Radha L.} and Annan Yang and Shuning He and Jinhua Wang and Ng, {Raymond W.S.} and Rita Sulahian and Lianbo Li and Poulin, {Emily J.} and Ling Huang and Jost Koren and Nora Dieguez-Martinez and Sergio Espinosa and Zhiyang Zeng and Corona, {Cesear R.} and Vasta, {James D.} and Ryoma Ohi and Taebo Sim and Kim, {Nam Doo} and Wayne Harshbarger and Lizcano, {Jose M.} and Robers, {Matthew B.} and Senthil Muthaswamy and Lin, {Charles Y.} and Look, {A. Thomas} and Haigis, {Kevin M.} and Mancias, {Joseph D.} and Wolpin, {Brian M.} and Aguirre, {Andrew J.} and Hahn, {William C.} and Westover, {Kenneth D.} and Gray, {Nathanael S.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = jun,

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doi = "10.1038/s41589-020-0506-0",

language = "English (US)",

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T1 - Discovery of a selective inhibitor of doublecortin like kinase 1

AU - Ferguson, Fleur M.

AU - Nabet, Behnam

AU - Raghavan, Srivatsan

AU - Liu, Yan

AU - Leggett, Alan L.

AU - Kuljanin, Miljan

AU - Kalekar, Radha L.

AU - Yang, Annan

AU - He, Shuning

AU - Wang, Jinhua

AU - Ng, Raymond W.S.

AU - Sulahian, Rita

AU - Li, Lianbo

AU - Poulin, Emily J.

AU - Huang, Ling

AU - Koren, Jost

AU - Dieguez-Martinez, Nora

AU - Espinosa, Sergio

AU - Zeng, Zhiyang

AU - Corona, Cesear R.

AU - Vasta, James D.

AU - Ohi, Ryoma

AU - Sim, Taebo

AU - Kim, Nam Doo

AU - Harshbarger, Wayne

AU - Lizcano, Jose M.

AU - Robers, Matthew B.

AU - Muthaswamy, Senthil

AU - Lin, Charles Y.

AU - Look, A. Thomas

AU - Haigis, Kevin M.

AU - Mancias, Joseph D.

AU - Wolpin, Brian M.

AU - Aguirre, Andrew J.

AU - Hahn, William C.

AU - Westover, Kenneth D.

AU - Gray, Nathanael S.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - 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 used chemoproteomic profiling and structure-based design to develop a 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. [Figure not available: see fulltext.].

AB - 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 used chemoproteomic profiling and structure-based design to develop a 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. [Figure not available: see fulltext.].

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JO - Nature chemical biology

JF - Nature chemical biology

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Discovery of a selective inhibitor of doublecortin like kinase 1

Abstract

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