Anti-inflammatory effects and joint protection in collagen-induced arthritis after treatment with IQ-1S, a selective c-Jun n-terminal kinase inhibitor

Igor A. Schepetkin, Liliya N. Kirpotina, Deepa Hammaker, Irina Kochetkova, Andrey Ivanovich Khlebnikov, Sergey A. Lyakhov, Gary S. Firestein, Mark T. Quinn

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22 Citations (Scopus)

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 11Hindeno[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.

Original languageEnglish
Pages (from-to)505-516
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number3
DOIs
Publication statusPublished - 1 Jun 2015

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ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

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