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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Pancreatic Ductal / drug therapy*
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Cell Line, Tumor
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Cell Movement
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Doublecortin Protein
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Doublecortin-Like Kinases
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Drug Screening Assays, Antitumor
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Gene Expression Regulation
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Mice
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Molecular Docking Simulation
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Molecular Structure
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Pancreatic Neoplasms / drug therapy*
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proteomics
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Rats
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Structure-Activity Relationship
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Zebrafish
Substances
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Dcx protein, rat
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Doublecortin Protein
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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DCLK1 protein, human
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Doublecortin-Like Kinases
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Protein Serine-Threonine Kinases