title: Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor.
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.
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Deepa
authors.initials: D
authors.lastname: Hammaker
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Irina
authors.initials: I
authors.lastname: Kochetkova
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Lyakhov
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.).
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., I.K., M.T.Q.); Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California (D.H., G.S.F.); Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.); Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia (A.I.K.); and A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine (S.A.L.) mquinn@montana.edu.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001665:Binding Sites / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D007596:Joints / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
chemical_list: C000599103:11H-indeno(1,2-b)quinoxalin-11-one oxime; D000906:Antibodies; D016207:Cytokines; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D048031:JNK Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases