Receptor-interacting-protein kinase 2 (RIP2) has been identified as a key signal transduction partner in the nucleotide oligomerization domain 2 (NOD2) pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. GSK2983559 is the first RIP2 kinase inhibitor to enter clinical trials, currently under phase 1 evaluation. VEGFR3 was the only kinase inhibited by more than 90% by GSK2983559. An additional 11 kinases were inhibited in the range of 70−89%. In a screen against non-kinase targets (Eurofins, 104 receptor and ion channel binding assays and 35 enzyme and cell-based assays), GSK2983559 was highly selective, inhibiting only melatonin receptor MT3 at a concentration under 10 μM. The in vivo efficacy of GSK2983559 was evaluated in a murine 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis model. Mice were dosed orally from days −2 to 5 at 0.25, 7.5, and 145 mg/kg b.i.d. which corresponds to predicted 10%, 50%, and 90% inhibition at 24 h, respectively. Further, administration of GSK2983559 at the 7.5 and 145 mg/kg b.i.d. doses exhibited efficacy similar to that of prednisolone as measured by summed colon scores[1].
GSK2983559 free acid 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Middle cerebral artery occlusion (MCAO) model
Intraventricular injection
3 μl of 200 μM for each Mice
Single dose 30 min before MCAO
GSK559 improved cerebral ischemic outcomes by inhibiting NF-κB activity and inflammatory response
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