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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 leveraged chemoproteomic profiling and structure-based design to develop the first 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140490 | GEO | 2020/04/06

REPOSITORIES: GEO

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Doublecortin-like kinase 1 activates NF-κB to induce inflammatory responses by binding directly to IKKβ

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