@article{f1a76ea4c2c04873a93ce8879f8754d8,
title = "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. [Figure not available: see fulltext.].",
keywords = "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",
author = "Ferguson, \{Fleur M.\} and Behnam Nabet and Srivatsan Raghavan and Yan Liu and Leggett, \{Alan L.\} and Miljan Kuljanin and Kalekar, \{Radha L.\} and Annan Yang and Shuning He and Jinhua Wang and Ng, \{Raymond W.S.\} and Rita Sulahian and Lianbo Li and Poulin, \{Emily J.\} and Ling Huang and Jost Koren and Nora Dieguez-Martinez and Sergio Espinosa and Zhiyang Zeng and Corona, \{Cesear R.\} and Vasta, \{James D.\} and Ryoma Ohi and Taebo Sim and Kim, \{Nam Doo\} and Wayne Harshbarger and Lizcano, \{Jose M.\} and Robers, \{Matthew B.\} and Senthil Muthaswamy and Lin, \{Charles Y.\} and Look, \{A. Thomas\} and Haigis, \{Kevin M.\} and Mancias, \{Joseph D.\} and Wolpin, \{Brian M.\} and Aguirre, \{Andrew J.\} and Hahn, \{William C.\} and Westover, \{Kenneth D.\} and Gray, \{Nathanael S.\}",
year = "2020",
month = jun,
day = "1",
doi = "10.1038/s41589-020-0506-0",
language = "Ingl{\'e}s estadounidense",
volume = "16",
pages = "635--643",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Research",
number = "6",
}
