1. Discovery of a selective inhibitor of doublecortin like kinase 1
- Author
-
Jinhua Wang, Senthil Muthaswamy, Kevin M. Haigis, Rita Sulahian, Kenneth D. Westover, Emily J. Poulin, Ryoma Ohi, Sergio Espinosa, Shuning He, Taebo Sim, Lianbo Li, Miljan Kuljanin, Nathanael S. Gray, Yan Liu, Nam Doo Kim, Joseph D. Mancias, Ling Huang, Brian M. Wolpin, Charles Y. Lin, Andrew J. Aguirre, Srivatsan Raghavan, Nora Diéguez-Martínez, Radha L. Kalekar, Jost Vrabic Koren, Zeng Zhiyang, Fleur M. Ferguson, James D Vasta, Behnam Nabet, William C. Hahn, Raymond W.S. Ng, Cesear Corona, Wayne Harshbarger, Alan L. Leggett, Matthew B. Robers, A. Thomas Look, Jose M. Lizcano, and Annan Yang
- Subjects
Male ,Proteomics ,Doublecortin Protein ,Protein Serine-Threonine Kinases ,Biology ,Article ,Transcriptome ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Doublecortin-Like Kinases ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,Organoid ,Animals ,Humans ,Protein Kinase Inhibitors ,Molecular Biology ,Zebrafish ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Molecular Structure ,Kinase ,030302 biochemistry & molecular biology ,Intracellular Signaling Peptides and Proteins ,Phosphoproteomics ,Cell Biology ,Rats ,Molecular Docking Simulation ,Pancreatic Neoplasms ,Gene Expression Regulation ,Protein kinase domain ,Cancer research ,Drug Screening Assays, Antitumor ,Carcinoma, Pancreatic Ductal - 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. A highly selective inhibitor of the DCLK1/2 kinases is used to uncover the consequences of DCLK1 inhibition on viability, phosphosignaling and the transcriptome in patient-derived organoid models of pancreatic ductal adenocarcinoma.
- Published
- 2020
- Full Text
- View/download PDF