☆ 4.5 Article

Designing a Small Fluorescent Inhibitor to Investigate Soluble Epoxide Hydrolase Engagement in Living Cells

ACS MEDICINAL CHEMISTRY LETTERS (2022)

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ACS MEDICINAL CHEMISTRY LETTERS
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AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00073

关键词

fluorescent tracer; soluble epoxide hydrolase; NanoBRET; assay development

类别

Chemistry, Medicinal

资金

  1. Alzheimer Forschung Initiative project [20041]
  2. Buchmann Fellowship
  3. Deutsche Forschungsgemeinschaft (DFG) [HI 2351/1-1, PR 1405/7-1, PR 1405/8-1, SFB 1039 TP A07, HE 6867/3-1]

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In this study, a small fluorescent sEH inhibitor was designed and showed excellent potency in vitro and the ability to visualize sEH in living cells.
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-CI) 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.

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