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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 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.

SUBMITTER: Ferguson FM 

PROVIDER: S-EPMC7246176 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Discovery of a selective inhibitor of doublecortin like kinase 1.

Ferguson Fleur M FM   Nabet Behnam B   Raghavan Srivatsan S   Liu Yan Y   Leggett Alan L AL   Kuljanin Miljan M   Kalekar Radha L RL   Yang Annan A   He Shuning S   Wang Jinhua J   Ng Raymond W S RWS   Sulahian Rita R   Li Lianbo L   Poulin Emily J EJ   Huang Ling L   Koren Jost J   Dieguez-Martinez Nora N   Espinosa Sergio S   Zeng Zhiyang Z   Corona Cesear R CR   Vasta James D JD   Ohi Ryoma R   Sim Taebo T   Kim Nam Doo ND   Harshbarger Wayne W   Lizcano Jose M JM   Robers Matthew B MB   Muthaswamy Senthil S   Lin Charles Y CY   Look A Thomas AT   Haigis Kevin M KM   Mancias Joseph D JD   Wolpin Brian M BM   Aguirre Andrew J AJ   Hahn William C WC   Westover Kenneth D KD   Gray Nathanael S NS  

Nature chemical biology 20200406 6

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  ...[more]

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