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

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. Fluorescen...

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Bibliographic Details
Published in:Angewandte Chemie 2019-10, Vol.131 (42), p.15142-15146
Main Authors: Fleming, Cassandra L., Sandoz, Patrick A., Inghardt, Tord, Önfelt, Björn, Grøtli, Morten, Andréasson, Joakim
Format: Article
Language:English
Subjects:
Binding
Chemistry
Diagnostic systems
Emission
Enzyme inhibitors
Experiments
Flow cytometry
Fluorescence
Fluoreszenz
Inhibitoren
Inhibitors
Kinasen
Kinases
Lck protein
Microscopy
Properties (attributes)
Solvatochromie
Titration
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Description
Summary: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. Ein fluoreszierender LCK‐Inhibitor wurde durch die Konjugation eines von Prodan abgeleiteten Fluorophors mit dem Pharmakophor eines ATP‐kompetitiven Kinase‐Inhibitors erhalten. Fluoreszenztitrationsexperimente zeigen die günstigen solvatochromen Eigenschaften des Inhibitors nach Bindung der Kinase. Mikroskopische und durchflusszytometrische Experimente belegen, dass die Fluoreszenzintensität des Inhibitors mit der LCK‐Konzentration korreliert.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201909536