All-photonic kinase inhibitors: light-controlled release-and-report inhibition

Light-responsive molecular tools targeting kinases affords one the opportunity to study the underlying cellular function of selected kinases. In efforts to externally control lymphocyte-specific protein tyrosine kinase (LCK) activity, the development of release-and-report LCK inhibitors is described...

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Bibliographic Details
Published in:	Chemical science (Cambridge) Vol. 15; no. 18; pp. 6897 - 695
Main Authors:	Fleming, Cassandra L, Benitez-Martin, Carlos, Bernson, Elin, Xu, Yongjin, Kristenson, Linnea, Inghardt, Tord, Lundbck, Thomas, Thorn, Fredrik B, Grtli, Morten, Andrasson, Joakim
Format:	Journal Article
Language:	English
Published:	England Royal Society of Chemistry 08-05-2024 The Royal Society of Chemistry
Subjects:	Cell membranes Chemical Sciences Chemistry Controlled release Coumarin Kemi Kinases Lymphocytes Photonics Tyrosine
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Summary:	Light-responsive molecular tools targeting kinases affords one the opportunity to study the underlying cellular function of selected kinases. In efforts to externally control lymphocyte-specific protein tyrosine kinase (LCK) activity, the development of release-and-report LCK inhibitors is described, in which (i) the release of the active kinase inhibitor can be controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the active kinase inhibitor. This introduces an unprecedented all-photonic method for users to both control and monitor real-time inhibitory activity. A functional cellular assay demonstrated light-mediated LCK inhibition in natural killer cells. The use of coumarin-derived caging groups resulted in rapid cellular uptake and non-specific intracellular localisation, while a BODIPY-derived caging group predominately localised in the cellular membrane. This concept of release-and-report inhibitors has the potential to be extended to other biorelevant targets where both spatiotemporal control in a cellular setting and a reporting mechanism would be beneficial. An all-photonic method is described, in which (i) the release of an active kinase inhibitor is controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the inhibitor to its corresponding target.
Bibliography:	https://doi.org/10.1039/d4sc00390j Electronic supplementary information (ESI) available: Synthetic procedures, NMR spectra, UV/vis absorption and emission spectra, cyclic voltammetry data, cellular and fluorescence bioimaging data. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-6520 2041-6539 2041-6539
DOI:	10.1039/d4sc00390j