A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis

• DOI: 10.1186/ar3329
• Publication Date: 2011-04-26T18:30:34Z
• Authors: Kristine L Stump; Lily D Lu; Pawel Dobrzanski; Cynthia Serdikoff; Diane E Gingrich; Ben J Dugan; Thelma S Angeles; Mark S Albom; Mark A Ator; Bruce D Dorsey; Bruce A Ruggeri; Matthew M Seavey
• Keywords: Proinflammatory cytokine

Janus kinase 2 (JAK2) is involved in the downstream activation of signal transducer and activator transcription 3 (STAT3) STAT5 responsible for transducing signals several proinflammatory cytokines pathogenesis rheumatoid arthritis (RA), including interleukin (IL)-6, interferon γ (IFNγ) IL-12. In this paper, we describe efficacy profile CEP-33779, a highly selective, orally active, small-molecule inhibitor JAK2 evaluated two mouse models RA.Collagen antibody-induced (CAIA) collagen type II (CII)-induced (CIA) were established before oral administration inhibitor, twice daily at 10 mg/kg, 30 55 mg/kg or 100 over period 4 to 8 weeks.Pharmacodynamic inhibition reduced mean paw edema clinical scores both CIA CAIA arthritis. Reduction (IL-12, IFNγ tumor necrosis factor α) serum (IL-12 IL-2) correlated with spleen CII-specific T helper 1 cell frequencies as measured by ex vivo enzyme-linked immunosorbent spot assay. Both demonstrated histological evidence disease amelioration upon treatment (for example, matrix erosion, subchondral osteolysis, pannus formation synovial inflammation) phosphorylated STAT3 levels. No changes body weight anti-CII autoantibody titers observed either RA model.This study demonstrates utility using potent bioavailable RA. Using selective rather than pan-JAK inhibitors avoids potential complication immunosuppression while targeting critical signaling pathways autoimmune progression.