R112

Description: R112 is a novel, potent and ATP-competitive inhibitor of Syk kinase with a Ki of 96 nM. R112 inhibited degranulation induced by anti-IgE cross-linking in mast cells (tryptase release, effective concentration for 50% inhibition EC(50) = 353 nmol/L) or basophils (histamine release, EC(50) = 280 nmol/L), and by allergen (dust mite) in basophils (histamine release, EC(50) = 490 nmol/L). R112 also blocked leukotriene C4 production and all proinflammatory cytokines tested. Subsequent molecular characterization indicated that R112 is an ATP-competitive spleen tyrosine kinase (Syk) inhibitor (inhibitory constant K(i) = 96 nmol/L). Its onset of action was immediate, and the inhibition was reversible. Incubation of mast cells with R112 showed that cytokine production in mast cells was dependent on sustained activation of the FcvarepsilonRI-Lyn-spleen tyrosine kinase pathway. Unlike other mast cell inhibitors, R112 was able to completely inhibit all three IgE-induced mast cell functions: degranulation, lipid mediator production, and cytokine production. R112 potently, completely, and rapidly abrogated all mast cell activation cascades triggered by IgE receptor cross-linking. R112 and its analogues offer a new modality in the treatment of allergic rhinitis.

References: J Allergy Clin Immunol. 2006 Sep; 118(3):749-755.