a highly selective, orally active inhibitor of janus kinase 2, cep-33779, ablates disease in two mouse models of rheumatoid arthritis高度选择性、口头活跃的杰纳斯激酶抑制剂2,cep - 33779,切除病两类风湿性关节炎的小鼠模型.pdfVIP

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a highly selective, orally active inhibitor of janus kinase 2, cep-33779, ablates disease in two mouse models of rheumatoid arthritis高度选择性、口头活跃的杰纳斯激酶抑制剂2,cep - 33779,切除病两类风湿性关节炎的小鼠模型.pdf

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a highly selective, orally active inhibitor of janus kinase 2, cep-33779, ablates disease in two mouse models of rheumatoid arthritis高度选择性、口头活跃的杰纳斯激酶抑制剂2,cep - 33779,切除病两类风湿性关节炎的小鼠模型

Stump et al. Arthritis Research Therapy 2011, 13:R68 /content/13/2/R68 RESEARCH ARTICLE Open Access A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis 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 and Matthew M Seavey Abstract Introduction: Janus kinase 2 (JAK2) is involved in the downstream activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), including interleukin (IL)-6, interferon g (IFNg) and IL-12. In this paper, we describe the efficacy profile of CEP-33779, a highly selective, orally active, small-molecule inhibitor of JAK2 evaluated in two mouse models of RA. Methods: Collagen antibody-induced arthritis (CAIA) and collagen type II (CII)-induced arthritis (CIA) were established before the oral administration of a small-molecule JAK2 inhibitor, CEP-33779, twice daily at 10 mg/kg, 30 mg/kg, 55 mg/kg or 100 mg/kg over a period of 4 to 8 weeks. Results: Pharmacodynamic inhibition of JAK2 reduced mean paw edema and clinical scores in both CIA and CAIA models of arthritis. Reduction in paw cytokines (IL-12, IFNg and tumor necrosis factor a) and serum cytokines (IL-12 and IL-2) correlated with reduced spleen CII-specific T helper 1 cell frequencies as measured by ex vivo IFNg enzyme-linked immunosorbent spot assay. Both models demonstrated histological evidence of disease amelioration upon treatment (for example, reduced matrix