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Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase

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Abstract

Altered expression or hyperactivation of anaplastic lymphoma kinase (ALK), as a consequence of translocations or point mutations, is one of the main oncogenic drivers in non-small cell lung cancer. Using structure-based design and in vitro enzyme assays, we identified 3-heteroarylcoumarin as a new template for the development of novel fluorescent ALK inhibitors. Molecular simulation provided structural insights for the design of 3-heteroarylcoumarin derivatives, which were easily prepared through efficient synthetic approaches including direct C–H cross coupling. Importantly, these coumarin-based ALK inhibitors can be tracked using microscopy techniques: we illustrated the use of the most potent compound in this series, 5a, (ALK/IC50 = 0.51 μM, λemi = 500 nm, ϕF = 0.29) to monitor its subcellular distribution pattern by confocal fluorescence microscopy.

Graphical abstract: Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase

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Publication details

The article was received on 17 Nov 2018, accepted on 05 Dec 2018 and first published on 06 Dec 2018


Article type: Paper
DOI: 10.1039/C8OB02874E
Citation: Org. Biomol. Chem., 2019, Advance Article
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    Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase

    S. Mah, J. Jang, D. Song, Y. Shin, M. Latif, Y. Jung and S. Hong, Org. Biomol. Chem., 2019, Advance Article , DOI: 10.1039/C8OB02874E

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