c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. In this study, the sodium salt of 11H[1,2-b]quinoxalin-11-one oxime (IQ-1S) was synthesized and shown to be a high-affinity JNK inhibitor. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1β in human fibroblast-like synoviocytes, and significantly attenuated development of murine collagen-induced arthritis. Collagen II–specific antibody responses were also reduced by IQ-1S treatment. In addition, IQ-1S treatment suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3+CD4+CD25+ regulatory T cells in lymph nodes.
See article at J Pharmacol Exp Ther 2015, 353:505–516.
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