Publication Date
6-1-2020
Journal
Nature Chemical Biology
DOI
10.1038/s41589-020-0506-0
PMID
32251410
PMCID
PMC7246176
PubMedCentral® Posted Date
10-6-2020
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Movement, Doublecortin Protein, Doublecortin-Like Kinases, Drug Screening Assays, Antitumor, Gene Expression Regulation, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Molecular Docking Simulation, Molecular Structure, Pancreatic Neoplasms, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Proteomics, Rats, Structure-Activity Relationship, Zebrafish
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.
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