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Spleen tyrosine kinase (Syk) is involved in regulation of B-cell receptor (BCR) and Fc receptor downstream signal pathways. Syk plays an essential role in production of inflammatory mediators and differentiation in various immune cells and is therefore an attractive target for treating inflammatory conditions, such as autoimmune and allergic diseases. We identified TAS05567 as a highly selective Syk inhibitor and evaluated its therapeutic potential in animal models. In vitro biochemical assays were performed with available kinase assay panels. Inhibitory effects of TAS05567 on immune cells were analyzed by assessing the Syk downstream signaling pathway and production of inflammatory factors. In vivo effects of TAS05567 were evaluated in animal models of autoimmune diseases and antigen-specific IgE transgenic mice. TAS05567 inhibited only 4 of 191 kinases tested but inhibited Syk enzymatic activity with high potency. TAS05567 inhibited BCR-dependent signal transduction in Ramos cells, Fc γ R-mediated tumor necrosis factor- α production in THP-1 cells, and Fc ε R-mediated histamine release from RBL-2H3 cells. In rheumatoid arthritis models, TAS05567 suppressed hind-paw swelling in a dose-dependent manner compared with vehicle. Moreover, TAS05667 markedly reduced histopathologic scores in an established rat arthritis model. In a mouse immune thrombocytopenic purpura model, platelet counts were reduced with injection of anti-platelet antibody. TAS05567 prevented the platelet count decrease in a dose-dependent manner. Finally, TAS05567 treatment suppressed IgE-mediated ear swelling in vivo. Collectively, our data indicate TAS05567 is a selective Syk inhibitor and potential therapeutic candidate for treating humoral immune-mediated inflammatory conditions such as autoimmune and allergic diseases.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models