Discovery of a Selective Inhibitor of Doublecortin Like Kinase 1

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2020 Apr 7

PMID 32251410

Citations 49

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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