Discovery of a selective inhibitor of doublecortin like kinase 1

Nat Chem Biol. 2020 Jun;16(6):635-643. doi: 10.1038/s41589-020-0506-0. Epub 2020 Apr 6.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Cell Line, Tumor
  • Cell Movement
  • Doublecortin Protein
  • Doublecortin-Like Kinases
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Pancreatic Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Proteomics
  • Rats
  • Structure-Activity Relationship
  • Zebrafish


  • Dcx protein, rat
  • Doublecortin Protein
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • DCLK1 protein, human
  • Doublecortin-Like Kinases
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Pancreatic Carcinoma