Discovery of a selective inhibitor of doublecortin like kinase 1.

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.

• Authors: 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 Corona, James 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
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 16 Issue 6 Pg. 635-643 (06 2020) ISSN: 1552-4469 [Electronic] United States
• PMID: 32251410 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, metabolism)
• Male
• Mice
• Molecular Docking Simulation
• Molecular Structure
• Pancreatic Neoplasms (drug therapy)
• Protein Kinase Inhibitors (chemistry, pharmacokinetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proteomics
• Rats
• Structure-Activity Relationship
• Zebrafish
• Pancreatic Neoplasms