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

Stump, Kristine; Lu, Lily; Dobrzański, Paweł; Serdikoff, Cynthia; Gingrich, Diane E.; Dugan, B.J.; Angeles, Thelma S.; Albom, Mark S.; Ator, Mark A.; Dorsey, Bruce D.; Ruggeri, Bruce; Seavey, Matthew M.

doi:10.1186/ar3329

Cited by 67 publications

(54 citation statements)

References 44 publications

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“…However, the formation of anti-collagen IgG was not affected in the sera of SB1578-treated mice. Thus, modulation of humoral immunity may not contribute to the observed therapeutic effects of SB1578 in the CIA model, consistent with two other reported JAK2 inhibitors (45,46).…”

Section: Discussionsupporting

confidence: 71%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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Section: Discussionsupporting

confidence: 71%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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“…7 The reductions in Th1 and Th17 responses with maintenance of Tregs after exposure to JAK2 inhibition are compatible with findings in mouse models of autoimmunity. 15,16 Whereas we found a significant decrease in the supernatant levels of IL-6 and TNF-␣ with TG101348 in the allogeneic MLRs, correlative studies in patients receiving TG101348 as part of a phase 1 trial in myelofibrosis did not show a suppressive effect on these proinflammatory cytokines. 22 These divergent findings may be because of cytokine variations in an allogeneic system in vitro compared with a noninflammatory state in vivo or to the inherent challenges of measuring accurate circulating cytokine levels in humans.…”

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confidence: 55%

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Betts

Abdel-Wahab

Curran

et al. 2011

Blood

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IntroductionGVHD is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Broadly acting immunosuppressants curtail lymphocyte alloreactivity, but they increase infectious complications and can jeopardize the GVL or graft-versus-tumor benefit of the transplantation. An ideal approach to preventing and treating GVHD would limit alloantigen-specific reactivity while preserving immunity against pathogens and malignant cells.The systemic dysregulation of inflammatory cytokines mediates the pathophysiology of GVHD, especially the acute form. 1 Among these cytokines, IL-6 has recently received increased attention because it promotes inflammation by suppressing regulatory T-cell (Treg) development and promoting Th17 expansion. 2-7 IL-6 also supports the maturation and activation of human dendritic cells (DCs). 8,9 Mouse HSCT models of GVHD have shown that IL-6 induces direct cytopathic damage to the intestinal epithelium. Its neutralization reduces gut pathology and improves survival, 10,11 probably because of the primacy of the gastrointestinal tract in amplifying systemic GVHD. 12 Targeting IL-6 with mAb or knock-out strategies, however, has resulted in discordant effects on the Treg/Th17 axis in these mouse models. 10,11 We have attempted to replicate the immunosuppressive effect of IL-6 inhibition in mice by studying primary human DC:T-cell interactions in vitro with tocilizumab, 13 a mAb to the IL-6 receptor-alpha (IL-6R-␣) subunit. Tocilizumab achieved the intended on-target effect of blocking IL-6 signaling in both monocytederived dendritic cells (moDCs) and T cells. There were no functional consequences, however, for moDC maturation, alloreactive T-cell proliferation, Treg expansion, or allogeneic Th1/Th17 responses in vitro. Therefore, inhibition of IL-6 by isolated receptor blockade would not limit alloreactivity in a human system. We therefore focused on Janus kinase-2 (JAK2), which relays the signaling function not only of IL-6R-␣, but also of other inflammatory cytokine receptors with relevance for allogeneic graft-host interactions. 14 The JAKs comprise a family of nonreceptor protein tyrosine kinases, which include JAK1, JAK2, JAK3, and Tyk2. These kinases associate with the cytoplasmic domains of cytokine receptors. 14 Upon their own phosphorylation, the JAKs induce downstream phosphorylation of signal transducer and activator of transcription (pSTAT) proteins. 14 Activated pSTATs in turn function as transcription factors that mediate cellular differentiation and growth. 14 JAK2 mediates T-cell signaling in response to various proinflammatory cytokines, including IL-6, IL-12, and IL-23. 14 These cytokines are critical to the development and expansion ofTh1 cells, which use IL-12, and Th17 cells, which use IL-6 and IL-23. 2,15,16 Th1 and Th17 cells can in turn induce alloreactive end organ damage in GVHD. 17 JAK2 is therefore a principle gatekeeper of The online version of this article contains a data supplement.The publication costs of this article wer...

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“…Full biochemical and molecular characterization of CEP-33779 is described elsewhere (24). CEP-33779 was provided orally in suspension form, dissolved in DMSO (1% final concentration; Sigma, St. Louis, MO), and further reconstituted in polyethylene glycol (PEG) 400 (Emerald BioSystems, Bainbridge Island, WA) to desired concentration for oral administration.…”

Section: Compoundmentioning

confidence: 99%

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Lu¹,

Stump²,

Wallace³

et al. 2011

The Journal of Immunology

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Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC50 = 1.3 nM; JAK3 enzyme IC50/JAK2 enzyme IC50 = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1β, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138+ plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.

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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

Cited by 67 publications

References 44 publications

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

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