JAK-IN-1是JAK1/2/3抑制剂，IC50分别为0.26，0.8和3.2nM。JAK-IN-1对JAK3的选择性比JAK1高。
JAK-IN-1 is a JAK1/2/3 inhibitor with IC50s of 0.26, 0.8 and 3.2 nM, respectively. JAK-IN-1 shows improved selectivity for JAK3 over JAK1.
JAK-IN-1 inhibits the proliferation of human CD4 and CD8 T cells in a dose-dependent manner upon stimulation by anti-CD3/anti-CD28 antibody-coated beads partially mimicking the activation signals brought to a Tcell by an antigen-presenting cell. JAK-IN-1 is active in both mechanistic and functional cell-based assays using T-cells, one of the major cell types in which JAK3 is potentially relevant[1].
JAK-IN-1 is JAK3 selective in vivo, as judged by higher potency inhibiting JAK1/JAK3- vs JAK2- or JAK1/JAK2/TYK2-driven signaling in whole blood assays. JAK-IN-1 potently inhibits IL-2 stimulated plasma concentrations of JAK-IN-1 for each dose. JAK-IN-1 prevents IL-2-driven STAT5 phosphorylation in a dose- and concentration-dependent manner, with approximately 50% inhibition observed at the 10 mg/kg dose (plasma concentration ～480 nM)[1].
[1]. Soth M, et al. 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. J Med Chem. 2013 Jan 10;56(1):345-56.
Cell experiment: | Carboxyfluorescein succinimidyl ester (CFSE)-labeled human PBMCs were exposed to JAK-IN-1 prior to stimulation with anti-CD3/anti-CD28 antibodies. Cell proliferation was then measured by CFSE dilutions as detected by flow cytometry in CD4 positive and CD8 positive T cells after staining with fluorochrome-conjugated antibodies[1] |
Animal experiment: | Mice[1]Adult (10?12 weeks old) C57BL/6 mice are treated with JAK-IN-1 (0.3, 1, 3, 10, 30, and 100 mg/kg). Mice received a single oral suspension dose of JAK-IN-1 or vehicle alone. Two hours after treatment by oral gavage, mice were euthanized for collecting whole blood in heparinized tubes[1]. |
参考文献: [1]. Soth M, et al. 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. J Med Chem. 2013 Jan 10;56(1):345-56. | |
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