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

Autor:	Fleming CL; Department of Chemistry and Chemical Engineering, Physical Chemistry, Chalmers University of Technology SE-41296 Göteborg Sweden a-son@chalmers.se.; Department of Chemistry and Molecular Biology, University of Gothenburg Box 462 SE-40530 Göteborg Sweden grotli@chem.gu.se., Benitez-Martin C; Department of Chemistry and Chemical Engineering, Physical Chemistry, Chalmers University of Technology SE-41296 Göteborg Sweden a-son@chalmers.se., Bernson E; TIMM Laboratory at Sahlgrenska Centre for Cancer Research, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg SE-41296 Göteborg Sweden., Xu Y; Department of Chemistry and Molecular Biology, University of Gothenburg Box 462 SE-40530 Göteborg Sweden grotli@chem.gu.se., Kristenson L; TIMM Laboratory, Sahlgrenska Centre for Cancer Research, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg SE-41296 Göteborg Sweden., Inghardt T; Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development, AstraZeneca SE-43183 Mölndal Sweden., Lundbäck T; Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca SE-43183 Mölndal Sweden., Thorén FB; TIMM Laboratory, Sahlgrenska Centre for Cancer Research, Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg SE-41296 Göteborg Sweden., Grøtli M; Department of Chemistry and Molecular Biology, University of Gothenburg Box 462 SE-40530 Göteborg Sweden grotli@chem.gu.se., Andréasson J; Department of Chemistry and Chemical Engineering, Physical Chemistry, Chalmers University of Technology SE-41296 Göteborg Sweden a-son@chalmers.se.
Jazyk:	angličtina
Zdroj:	Chemical science [Chem Sci] 2024 Apr 12; Vol. 15 (18), pp. 6897-6905. Date of Electronic Publication: 2024 Apr 12 (Print Publication: 2024).
DOI:	10.1039/d4sc00390j
Abstrakt:	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. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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