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

Frederico S L M Rodrigues, Xueyan Yang, Masataka Nikaido, Qingsong Liu, Robert N Kelsh

Research output: Contribution to journalArticle

8 Citations (Scopus)
107 Downloads (Pure)

Abstract

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.
Original languageEnglish
Pages (from-to)1968-1974
Number of pages7
JournalACS Chemical Biology
Volume7
Issue number12
Early online date16 Sep 2012
DOIs
Publication statusPublished - 21 Dec 2012

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