Gene

Kinase

Context (archaeology)

Cell biology

Doublecortin

Protein-Serine-Threonine Kinases

Neuroscience

Biology

Phosphoproteomics

Hippocampal formation

Protein phosphorylation

Cancer research

Biochemistry

Protein kinase A

Pancreatic cancer

Computational biology

Drug discovery

Paleontology

Genetics

Transcriptome

Bioinformatics

Dentate gyrus

Chemistry

Proteomics

Cancer

Gene expression

Nature Chemical Biology

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.

Discovery of a selective inhibitor of doublecortin like kinase 1