Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
SB1578, a Novel Selective JAK2 Inhibitor, Is Highly Efficacious in Rodent Models of Rheumatoid Arthritis.
Chuan Goh, Kee, Hart, Stefan, Kiang Loh, Yung, Cheng Tan, Yong, Amalini, Chithra, Jayaraman, Ramesh, Ethirajulu, Kantharaj
JAK2, a member of the Janus kinase family, is a key component in the signaling pathways elicited by pro-inflammatory cytokines such as interferon-g, interleukin-6, interleukin-12 and interleukin-23. These cytokines, in different sequence and combinations with other factors, initiate and/or sustain the T-helper cell subsets activated during autoimmune inflammatory diseases. The JAK2 kinase may therefore serve as a useful target for pharmacological intervention in some of these diseases, including rheumatoid arthritis (RA). We report here SB1578, a novel JAK2 inhibitor which demonstrates a unique kinase spectrum, activity on cellular biomarkers, favorable pharmacokinetic and in vitro safety profile, and promising activity in 2 rodent models of rheumatoid arthritis.
In vitro potency of SB1578 against a diverse panel of kinases was evaluated using recombinant enzymes with synthetic substrates. Potency on intracellular signaling pathways was assessed by Western blot analyses of the phosphorylated substrates in cell lysates. Viability assays were performed on tumor cell lines to investigate potential anti-proliferative activity. In vivo efficacy was tested in a rat model of adjuvant-induced arthritis and a mouse model of collagen-induced arthritis.
SB1578 was shown to be a potent inhibitor of JAK2 (IC50= 46 nM) as well as two other kinases reported to be implicated in human rheumatoid arthritis, namely FLT3 and CSF-1R (IC50= 62 nM and 69 nM respectively). In a panel of 25 cell lines, SB1578 selectively inhibits proliferation in cell lines with a known dependence on JAK2 or FLT3 signaling, whether wild-type or mutated. These include MV411, Molm13, 32D, and BaF3 cells with transfected wild-type or mutant JAK2 (IC50 from 39 to 500 nM). Phosphoblot analysis in these cells showed that FLT3 or JAK2 signaling pathways are blocked in a dose-dependent manner. In a Lewis rat model of adjuvant-induced arthritis, administration of SB1578 (20 and 40 mg/kg BID, i.p.) led to dose-related reductions toward normal for histopathologic bone resorption, paw inflammation, ankle measurements, and splenic inflammation. In a B10RIII murine model of collagen-induced arthritis, oral administration of SB1578 (100, 200 and 300 mg/kg BID) led to dose-dependent reductions of clinical arthritis scores and hallmarks of mouse CIA model, including pannus formation and histological joint damage. The highest dose of 300 mg/kg BID led to zero disease incidence in terms of paw inflammation and histological parameters. Analyses of terminal serum samples showed that two cytokines, IL-6 and the chemokine KC, were significantly elevated in diseased compared with normal mice, and levels of these two cytokines were normalized by treatment with SB1578. Studies on primary PBMCs to illustrate the effects of SB1578 on Th1 and Th17 pathways will also be reported.
SB1578, a novel and selective JAK2 inhibitor, has demonstrated promising on-target activities in JAK2-dependent cell lines and is highly efficacious in two rodent models of rheumatoid arthritis. It is currently undergoing final preclinical development activities to prepare it for clinical studies.
To cite this abstract, please use the following information:
Chuan Goh, Kee, Hart, Stefan, Kiang Loh, Yung, Cheng Tan, Yong, Amalini, Chithra, Jayaraman, Ramesh, et al; SB1578, a Novel Selective JAK2 Inhibitor, Is Highly Efficacious in Rodent Models of Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :717