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

Mah, Shinmee; Jang, Jaebong; Song, Daesun; Shin, Yongje; Latif, Muhammad; Jung, Yongwon; Hong, Sungwoo.
Org Biomol Chem; 17(1): 186-194, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30534706
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.
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