R406 (free base)

R406 is a potent Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. IC50 value: 41 nM [1]Target: Syk in vitro: R406 is a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling. R406 inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8, and GM-CSF. R406 inhibits phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 binds to the ATP binding pocket of Syk and inhibits its kinase activity as an ATP-competitive inhibitor with Ki of 30 nM. R406 blocks Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and Bcr-mediated activation of B lymphocytes [1]. R406 significantly induces chronic lymphocytic leukemia (CLL) cell apoptosis in nurselike cells cocultures and blocks CCL3 and CCL4 secretion by CLL cells in response to B-cell antigen receptor (Bcr) triggering [2]. R406 is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross-linking by specific antibodies or by sera from HIT patients [3].in vivo: R406 reduces cutaneous reverse passive Arthus reaction by approximately 86% at 5 mg/kg in prophylactic treated mice. R406 also shows efficacy in inhibiting paw inflammation in antibody-induced arthritis mouse models [1]. R406 does not adversely affect macrophage or neutrophil function in innate immune responses and has minimal functional immunotoxicity notwithstanding its lymphocytopenic effect [4].

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Syk

Research Areas >> Inflammation/Immunology

[1]. Braselmann S, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther, 2006, 319(3), 998-1008.

[2]. Quiroga MP, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood, 2009, 114(5), 1029-1037.

[3]. Lhermusier T, et al. The Syk-kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin-PF4 complex directed antibodies. J Thromb Haemost, 2011, 9(10), 2067-2076.

[4]. Zhu Y, et al. Immunotoxicity assessment for the novel Spleen tyrosine kinase inhibitor R406. Toxicol Appl Pharmacol, 2007, 221(3), 268-277.

Entospletinib | cerdulatinib | Piceatannol | BAY-61-3606 | R788 (disodium hexahydrate) | R406 | PRT062607 (P505-15, BIIB057) HCl | TAK-659 hydrochloride | PRT-060318 | RO9021 | ASN-002 | MDBN | R 112