A simple, highly visual in vivo screen for anaplastic lymphoma kinase inhibitors. 2012

Frederico S L M Rodrigues, and Xueyan Yang, and Masataka Nikaido, and Qingsong Liu, and Robert N Kelsh
Centre for Regenerative Medicine and Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.

Anaplastic lymphoma kinase (ALK) is an important drug target in many cancers, including lymphoma, neuroblastoma, and lung cancer. Here, we demonstrate proof-of-principle for a novel and inexpensive assay for ALK inhibitor activity and identification in zebrafish. We demonstrate that the human oncogenic ALK fusion, NPM-ALK, drives overproduction of iridophores, a highly visible, shiny pigment cell-type in zebrafish. Treatment with the potent ALK inhibitor, TAE684, fully inhibits production of ALK-dependent iridophores. Using our assay, we test multiple properties of TAE684 in vivo, including efficacy, specificity, and toxicity. We note that TAE684 also inhibits the closely related leukocyte tyrosine kinase (Ltk) that is required for endogenous iridophore development. Similar effects are observed with an independent inhibitor, Crizotinib. Our assay can thus be utilized to identify ALK or LTK inhibitors. Importantly, the natural reflectivity of iridophores lends itself to automation for high throughput assessment of ALK and LTK inhibitor compounds in vivo.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000077548 Anaplastic Lymphoma Kinase A receptor tyrosine kinase that is essential for development and differentiation of the nervous system in response to secreted growth factors. It phosphorylates the first tyrosine of the Y-x-x-x-Y-Y motif of targets that include PROTO-ONCOGENE PROTEINS C-CBL; INSULIN RECEPTOR SUBSTRATE-1; and MITOGEN-ACTIVATED PROTEIN KINASES, leading to activation of the MAPK signaling pathway and cell proliferation. A chromosomal aberration involving the ALK gene results in its constitutive expression in some cases of NON-HODGKIN LYMPHOMA. ALK Kinase,ALK Tyrosine Kinase Receptor,Anaplastic Lymphoma Receptor Tyrosine Kinase,CD246 Antigen,NPM-ALK,Nucleophosmin-Anaplastic Lymphoma Kinase,Nucleophosmin Anaplastic Lymphoma Kinase
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015027 Zebrafish An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research. Brachydanio rerio,Danio rerio,B. rerio,D. rerio,Zebra Fish,Zebra Fishes,Zebra danio,Zebrafishes,D. rerios,Fishes, Zebra,Zebra danios,danio, Zebra
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D020794 Receptor Protein-Tyrosine Kinases A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity. PTK Receptor,Receptors, Protein-Tyrosine Kinase,Tyrosine Kinase Linked Receptor,Tyrosine Kinase Linked Receptors,Tyrosine Kinase Receptor,Tyrosine Kinase Receptors,PTK Receptors,Protein-Tyrosine Kinase Receptor,Receptor Protein-Tyrosine Kinase,Kinase Receptor, Tyrosine,Kinase, Receptor Protein-Tyrosine,Kinases, Receptor Protein-Tyrosine,Protein-Tyrosine Kinase Receptors,Protein-Tyrosine Kinase, Receptor,Protein-Tyrosine Kinases, Receptor,Receptor Protein Tyrosine Kinase,Receptor Protein Tyrosine Kinases,Receptor, PTK,Receptor, Protein-Tyrosine Kinase,Receptor, Tyrosine Kinase,Receptors, PTK,Receptors, Protein Tyrosine Kinase

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