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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish
Pages (from-to)635-643
Number of pages9
JournalNature Chemical Biology
Volume16
Issue number6
DOIs
Publication statusPublished - 2020 Jun 1

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