fostamatinib and Inflammation

IgA nephropathy is the most common type of primary glomerulonephritis worldwide. At least 25% of patients may progress to kidney failure requiring dialysis or transplantation. Treatment of IgA nephropathy using generalized immunosuppression is controversial, with concerns regarding the balance of safety and efficacy in a nonspecific approach. This review describes the recent scientific evidence, and a current clinical trial, investigating whether spleen tyrosine kinase (SYK) may be a novel and selective therapeutic target for IgA nephropathy. SYK, a cytoplasmic tyrosine kinase, has a pivotal role as an early intermediate in intracellular signal transduction cascades for the B-cell receptor and the immunoglobulin Fc receptor, and thus is critical for B-cell proliferation, differentiation, and activation, and for mediating proinflammatory responses after Fc-receptor engagement in various cell types. In renal biopsy specimens of patients with IgA nephropathy, increased expression and phosphorylation of SYK were detected, and this correlated with the histologic features of mesangial and endocapillary proliferation. In cell culture studies, patient-derived IgA1 stimulated mesangial cell SYK activation, cell proliferation, and cytokine production, and these responses were attenuated by pharmacologic or molecular inhibition of SYK. A global, randomized, double-blind, placebo-controlled trial investigating the safety and efficacy of fostamatinib (an oral prodrug SYK inhibitor) in the treatment of patients with IgA nephropathy is ongoing, which may provide important evidence of the safety and efficacy of targeting this pathway in clinical disease.

Topics: Aminopyridines; B-Lymphocytes; Capillaries; Cell Proliferation; Cytokines; Glomerulonephritis, IGA; Humans; Inflammation; Mesangial Cells; Molecular Targeted Therapy; Morpholines; Oxazines; Pyridines; Pyrimidines; Receptors, Fc; Signal Transduction; Syk Kinase

Registries estimate that one third of patients with psoriatic arthritis (PsA) are "resistant" to of TNF-alpha blockers. Therefore, the search for new approaches to treatment of this disease may be justified. Currently the treatment options that have proven effective are associated with inhibition of the T cell costimulatory pathway (abatacept and alefacept) and blocking the P40 fraction of IL-12 and IL-23 (ustekinumab). A novel pathway inhibition, which deserves special attention is offered by apremilast. This molecule inhibits phosphodiesterase IV, responsible for hydrolyzing cyclic adenosine monophosphate to adenosine monophosphate, which causes an increase in cAMP. This metabolite is associated with decreased TNF-alpha. It has a modest efficacy (ACR 20 response of 43%), and subsequent studies have shown an improvement in visual analog scale and the SF36 compared to placebo. Currently there are five clinical trials in phase III to assess its effectiveness in parameters of inflammation and radiographic progression. The spectrum of possibilities before treatment failure with anti-TNF alpha, is augmented by the appearance of several reports that show efficacy with the individual use of CD20 inhibitors and IL-1. In patients with rheumatoid arthritis (RA) the effectiveness of molecules that inhibit signal transduction of cytokines (Anti-JAK) has been proven, so it is possible that in the future they may be used in patients with PsA.

Topics: Aminopyridines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antirheumatic Agents; Arthritis, Psoriatic; Bone Remodeling; Clinical Trials, Phase III as Topic; Cyclic AMP; Cytokines; Denosumab; Disease Progression; Drug Resistance; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Janus Kinases; Lymphocyte Activation; Lymphocyte Depletion; Molecular Targeted Therapy; Morpholines; Oxazines; Phosphodiesterase 4 Inhibitors; Pyridines; Pyrimidines; T-Lymphocyte Subsets; Thalidomide; Treatment Outcome; Tumor Necrosis Factor-alpha

Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.

Topics: Aminopyridines; Animals; ErbB Receptors; Gefitinib; Inflammation; Mice; Morpholines; Pulmonary Fibrosis; Pyridines; Pyrimidines; Silicosis

Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development.. Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet -induced monocytosis and inflammatory gene expression.. We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis.

Topics: Administration, Oral; Aminopyridines; Animals; Atherosclerosis; Cell Differentiation; Cell Movement; Cholesterol, Dietary; Inflammation; Intracellular Signaling Peptides and Proteins; Macrophages; Mice; Morpholines; Oxazines; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Receptors, LDL; Syk Kinase

Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.

Topics: Aminopyridines; Animals; Arthritis, Rheumatoid; Arthus Reaction; Bone Resorption; Collagen Type II; Disease Models, Animal; Female; Immunoglobulin G; Inflammation; Intracellular Signaling Peptides and Proteins; Morpholines; Oxazines; Prodrugs; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, IgG; Signal Transduction; Syk Kinase; Synovial Fluid; Synovitis