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Fleming CL, Benitez-Martin C, Bernson E, Xu Y, Kristenson L, Inghardt T, Lundbäck T, Thorén FB, Grøtli M, Andréasson J
Chem. Sci. 15 (18) 6897-6905 [2024-05-08; online 2024-04-12]
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.
Integrated Microscopy Technologies Gothenburg [Service]
PubMed 38725520
DOI 10.1039/d4sc00390j
Crossref 10.1039/d4sc00390j
pmc: PMC11077529
pii: d4sc00390j