title: Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor.
abstract: Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.
authors.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., San Francisco, CA 94080, USA.
authors.forename: Polly R
authors.initials: PR
authors.lastname: Pine
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.forename: Nathan
authors.initials: N
authors.lastname: Schoettler
authors.forename: Mona L
authors.initials: ML
authors.lastname: Banquerigo
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.forename: Angela
authors.initials: A
authors.lastname: Lau
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhao
authors.forename: Elliott B
authors.initials: EB
authors.lastname: Grossbard
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Ernest
authors.initials: E
authors.lastname: Brahn
mesh_terms: D000631:Aminopyridines; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001183:Arthus Reaction / Q000188:drug therapy; D001862:Bone Resorption / Q000517:prevention & control*; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000072377:Syk Kinase; D013582:Synovial Fluid / Q000276:immunology; D013585:Synovitis / Q000188:drug therapy
chemical_list: D000631:Aminopyridines; D024043:Collagen Type II; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011355:Prodrugs; D011725:Pyridines; D011743:Pyrimidines; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat; C523665:fostamatinib