A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding

被引:17
作者
Fleming, Cassandra L. [1 ,2 ]
Sandoz, Patrick A. [3 ]
Inghardt, Tord [4 ]
Onfelt, Bjorn [3 ,5 ]
Grotli, Morten [2 ]
Andreasson, Joakim [1 ]
机构
[1] Chalmers Univ Technol, Dept Chem & Chem Engn Phys Chem, S-41296 Gothenburg, Sweden
[2] Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden
[3] KTH Royal Inst Technol, Sci Life Lab, Dept Appl Phys, S-10691 Stockholm, Sweden
[4] AstraZeneca, Med Chem, Res & Early Dev Cardiovasc Renal & Metab, BioPharmaceut R&D, Gothenburg, Sweden
[5] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden
基金
欧盟地平线“2020”; 瑞典研究理事会;
关键词
fluorescence; inhibitors; kinase; solvatochromism; PLASMA-MEMBRANE; PROBE; LCK; PRODAN; DYES; DISCOVERY; PROTEIN; DESIGN; POTENT; DNA;
D O I
10.1002/anie.201909536
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The development of a fluorescent LCK inhibitor that exhibits favourable solvatochromic properties upon binding the kinase is described. Fluorescent properties were realised through the inclusion of a prodan-derived fluorophore into the pharmacophore of an ATP-competitive kinase inhibitor. Fluorescence titration experiments demonstrate the solvatochromic properties of the inhibitor, in which dramatic increase in emission intensity and hypsochromic shift in emission maxima are clearly observed upon binding LCK. Microscopy experiments in cellular contexts together with flow cytometry show that the fluorescence intensity of the inhibitor correlates with the LCK concentration. Furthermore, multiphoton microscopy experiments demonstrate both the rapid cellular uptake of the inhibitor and that the two-photon cross section of the inhibitor is amenable for excitation at 700 nm.
引用
收藏
页码:15000 / 15004
页数:5
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