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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)


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 languageAmerican English
Pages (from-to)635-643
Number of pages14
JournalNature Chemical Biology
Issue number6
Publication statusPublished - 1 Jun 2020


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


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