Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

J Pharmacol Exp Ther. 2015 Jun;353(3):505-16. doi: 10.1124/jpet.114.220251. Epub 2015 Mar 17.

Abstract

c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. 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 (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also 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. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies / analysis
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology
  • Binding Sites / drug effects
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Joints / pathology
  • Male
  • Matrix Metalloproteinases / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Oximes / pharmacology*
  • Oximes / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinoxalines / pharmacology*
  • Quinoxalines / therapeutic use
  • Synovial Fluid / cytology
  • Synovial Fluid / metabolism
  • T-Lymphocytes, Regulatory / drug effects

Substances

  • 11H-indeno(1,2-b)quinoxalin-11-one oxime
  • Antibodies
  • Cytokines
  • Oximes
  • Protein Kinase Inhibitors
  • Quinoxalines
  • JNK Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinases