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ID: ALA5120942
Journal: ACS Med Chem Lett
Title: Designing a Small Fluorescent Inhibitor to Investigate Soluble Epoxide Hydrolase Engagement in Living Cells.
Authors: Brunst S, Schönfeld J, Breunig P, Burgers LD, DeMeglio M, Ehrler JHM, Lillich FF, Weizel L, Hefendehl JK, Fürst R, Proschak E, Hiesinger K.
Abstract: Soluble epoxide hydrolase (sEH) is a promising target for a number of inflammation-related diseases. In addition, inhibition of sEH has been shown to reduce neuroinflammation, which plays a critical role in the development of central nervous system (CNS) diseases such as Alzheimer's disease. In this study, we present the rational design of a small fluorescent sEH inhibitor. Starting from the clinical candidate GSK2256294A, we replaced the triazine moiety with the 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) fluorophore. The resulting fluorescent sEH inhibitor displayed excellent potency in an in vitro enzyme activity assay (IC50 < 2 nM). The developed inhibitor is applicable in a NanoBRET-based assay system suitable for studying sEH target engagement in living cells. Furthermore, the inhibitor can be used to visualize sEH in sEH-transfected HEK293 cells and in primary mouse astrocytes by fluorescence microscopy.
CiteXplore: 35859883