目的 评价小分子化合物FZJ-003对Janus激酶(janus kinase,JAK)活性的抑制作用以及对类风湿性关节炎(rheumatoid arthritis,RA)的治疗作用。方法 在体外激酶、细胞以及人全血水平上,评估FZJ-003对JAK1,JAK2,JAK3和TYK2的抑制活性。建立大鼠RA关节炎模型,采用不同剂量的FZJ-003对关节炎模型大鼠进行给药,通过关节炎评分、X-射线影像分析和组织病理学检查,以及血清样本中的炎症细胞因子的变化,考察化合物对关节炎的治疗效果。结果 体外激酶、细胞和人全血水平的分析结果显示,FZJ-003在JAK1的抑制活性较强,模板分子Filgotinib的抑制作用较弱,在JAK1/JAK2选择性上与Filgotinib相近。对佐剂诱导LEWIS大鼠关节炎(AIA)的治疗作用的研究结果显示,FZJ-003能有效控制大鼠AIA的疾病发展,降低血液中的炎症因子,抑制炎症、关节囊膜增生和软骨下骨破坏等病理学改变。结论 FZJ-003分子能选择性抑制JAK1活性,对大鼠RA模型有一定的治疗效果,是合适的药物开发候选分子。
Abstract
OBJECTIVE To characterize the inhibitory effects of FZJ-003 on janus kinases (JAKs) and the therapeutic efficacy on rheumatoid arthritis (RA). METHODS The potency and selectivity of FZJ-003 on JAK1, JAK2, JAK3 and TYK2 were analyzed with biochemical assays, cellular assays, and human whole blood assays (WBAs), respectively. The rat RA models were constructed and treated with different dosage of FZJ-003. Joint injury was evaluated with X-ray imaging and pathological analysis. The serum concentrations of some proinflammatory cytokines were measured. RESULTS The potency of FZJ-003 on JAK1 inhibition was higher than filgotinib, whereas the JAK1/2 selectivity was comparable to that of filgotinib. FZJ-003 could effectively control the disease development of AIA in rats by reducing the inflammatory cytokines, inhibiting inflammation, synovial membrane hyperplasia, cartilage lesion and bone erosion. CONCLUSION FZJ-003 can selectively inhibit JAK1 activity and is effective in the treatment of rat RA model. It is a candidate molecule for drug development.
关键词
类风湿性关节炎 /
JAK抑制剂 /
JAK/STAT通路 /
JAK1/JAK2选择性 /
炎症因子 /
药效
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Key words
rheumatoid arthritis /
JAK inhibitor /
JAK/STAT signaling pathway /
JAK1/JAK2 selectivity /
proinflammatory cytokine /
therapeutic efficacy
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中图分类号：
R965
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参考文献
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