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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Constitutively activated STAT3 and STAT5 are expressed in a wide variety of human malignancies including solid and hematopoietic cancers and often correlate with a poor prognosis and resistance to multiple therapies. Given the well established role of STAT3 in tumorigenesis, inhibition of Janus-activated kinase 2 (JAK2) activity might represent an attractive therapeutic approach. Using a mouse model of colitis-induced colorectal cancer, we show that a novel, orally active, selective JAK2 inhibitor, CEP-33779, induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells. Histopathologic analysis confirmed reduced incidence of histologic-grade neoplasia by CEP-33779. Tumor regression correlated with inhibition of STAT3 and NF-kB (RelA/p65) activation in a CEP-33779 dose-dependent manner. In addition, the expression of proinflammatory, tumor-promoting cytokines interleukin (IL)-6 and IL-1b was strongly reduced upon JAK2 inhibition. The ability of CEP-33779 to suppress growth of colorectal tumors by inhibiting the IL-6/JAK2/STAT3 signaling suggests a potential therapeutic utility of JAK2 inhibitors in multiple tumors types, particularly those with a strong inflammatory component.

Since therapeutic blockade of the cellular proteasome has previously demonstrated preclinical efficacy against inflammatory diseases, the evaluation of a novel, orally active proteosome inhibitor, CEP-18770, was tested in models of systemic lupus erythematosus (SLE). Age matched, 8-week old (MRL/lpr) or 8 months old (NZM) mice with established SLE or lupus nephritis (LN), respectively, were treated with CEP-18770 either 3mg/kg 1-2x/wk, iv, or orally at 10mg/kg. Reference agent, bortezomib, was provided at 0.5mg/kg, 1x/wk, or 0.3mg/kg 1-2x/wk. Standard of care agents included dexamethasone or cyclophosphamide. Mice were monitored for clinical, pathological and immunological changes. Reductions in the frequencies of specific anti-chromatin, smith and dsDNA antibody secreting cells (ASC) and levels of the corresponding antinuclear antibodies (ANA), followed CEP-18770 treatment and were accompanied by decreases in spleen ASCs, plasma cells, and serum cytokines (IL-12, IL-17A, IL-1β, TNFα). CEP-18770-treatment also mitigated the incidence of renal histopathology, and subsequently, proteinuria, in both models. CEP-18770 treatment also extended survival for both models over bortezomib. Proteasome inhibition and IκBα accumulation in target tissues followed administration of CEP-18770 and bortezomib. CEP-18770 was equivalent to treatment with bortezomib; however, CEP-18770 resulted in greater tolerability and rate of response resulting in greater SLE disease stability overtime.