JTE-852, a novel spleen tyrosine kinase inhibitor, blocks mediator secretion from mast cells with immunoglobulin E crosslinking

Abstract

Mast cells stimulated by immunoglobulin E (IgE)-crosslinking secrete mediators, which are mainly categorized into three groups: granule contents, arachidonate metabolites, and cytokines. These mediators play important roles in pathogenesis of allergic diseases; indeed, some conventional drugs which target the mediators are used in clinical practices. However, these drugs are not yet sufficient enough in their efficacy. That is because most of them are blockers of single mediators and are unable to prevent simultaneously various reactions caused by the three group mediators. Spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase. In mast cells, Syk locates at almost top of the signal cascades induced by IgE-crosslinking and plays pivotal roles in secretion of the three groups of mediators. Therefore, inhibition of Syk would suppress the secretion of all the mediators from mast cells and be a promising-treatment strategy for allergic diseases. In the present study, we characterized pharmacological profiles of JTE-852, which was identified as a novel Syk inhibitor. JTE-852 inhibited kinase activity of Syk in an adenosine 5′-triphosphate (ATP)-competitive fashion. JTE-852 also blocked the secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by IgE-crosslinking, with similar potencies. The results suggest that JTE-852 is supposed to prevent various allergic reactions caused by the three group mediators in vivo. In fact, oral gavage of JTE-852 attenuated an allergic reaction mediated by histamine, which is a representative of the three groups of mediators. JTE-852 is expected to be a novel, highly-efficacious, and orally available anti-allergic drug.