6-[[5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (CAS 841290-80-0)

6-[[5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one, also recognized as R406, is a powerful ATP-competitive inhibitor of spleen tyrosine kinase (Syk, Ki = 30 nM). Its action inhibits FcεRI-dependent mast cell activation (EC50 = 43 nM), and when applied at 3 μM, it diminishes the release of IL-10, -12, and -13 by immune complex-pulsed dendritic cells. When confronting cancers characterized by Syk over-expression, R406 has the capability to interrupt signaling downstream of Syk, leading to apoptosis. Furthermore, 6-[[5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one can block Syk-dependent signaling through c-Jun N-terminal kinase in rheumatoid arthritis synoviocytes, which hints at a potential intervention in this autoimmune disease. 6-[[5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one is an effective inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC for degranulation = 56-64 nM). Its primary target is the spleen tyrosine kinase (Syk). R406 inhibits phosphorylation of the Syk substrate linker for activation of T cells in mast cells, and B-cell linker protein/SLP65 in B cells. It binds to the ATP binding pocket of Syk, inhibiting its kinase activity.