title: A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis.
abstract: BACKGROUND
  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 γ (IFNγ) 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, IFNγ and tumor necrosis factor α) and serum cytokines (IL-12 and IL-2) correlated with reduced spleen CII-specific T helper 1 cell frequencies as measured by ex vivo IFNγ enzyme-linked immunosorbent spot assay. Both models demonstrated histological evidence of disease amelioration upon treatment (for example, reduced matrix erosion, subchondral osteolysis, pannus formation and synovial inflammation) and reduced paw phosphorylated STAT3 levels. No changes in body weight or serum anti-CII autoantibody titers were observed in either RA model.
  
  
  CONCLUSIONS
  This study demonstrates the utility of using a potent and highly selective, orally bioavailable JAK2 inhibitor for the treatment of RA. Using a selective inhibitor of JAK2 rather than pan-JAK inhibitors avoids the potential complication of immunosuppression while targeting critical signaling pathways involved in autoimmune disease progression.
authors.affiliation: Cephalon, Inc., Research Drug Discovery, 145 Brandywine Parkway, Building 200, West Chester, PA 19380-4249, USA.
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Stump
authors.forename: Lily D
authors.initials: LD
authors.lastname: Lu
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzanski
authors.forename: Cynthia
authors.initials: C
authors.lastname: Serdikoff
authors.forename: Diane E
authors.initials: DE
authors.lastname: Gingrich
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Dugan
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Seavey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D008811:Mice, Inbred DBA; D011725:Pyridines / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D000893:Anti-Inflammatory Agents; C567989:CEP 33779; D004791:Enzyme Inhibitors; D011725:Pyridines; D014230:Triazoles; D053614:Janus Kinase 2