CLR Inhibitor

R406 (the active metabolite of Fostamatinib) is a specific, ATP-competitive inhibitor of the spleen tyrosine kinase (Syk), a cytosolic enzyme that plays a key role in innate and adaptive immunity. 

Mode of action:

R406 competes with ATP for binding to the catalytic site in the kinase domain and thus inhibits Syk signaling pathways [1]. Syk is widely known for its role in relaying adaptive immune receptor signaling. It also participates in innate recognition of fungal and other microbial pathogens by C-type lectin receptors (CLRs) such as Dectin-1, Dectin-2, and Mincle. Syk activation by CLRs triggers the caspase-recruitment domain 9 (CARD9) pathway leading to the induction of pro-inflammatory cytokines. Syk is also required for NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation following fungal infection. 

Treatment with R406 effectively inhibits CLR-mediated cytokine secretion in immune cells [2, 3]. R406 also selectively abrogates inflammasome activation by C. albicans but not by inflammasome activators such as the bacterial toxin nigericin [4].

Furthermore, through its inhibitory action, R406 has been shown to potently block IgE- and IgG-mediated activation of Fc receptor signaling and reduce inflammation in experimental models of arthritis [1].

Of note, in cancers characterized by over-expression of Syk, R406 treatment induces the activation of caspase leading to significant apoptosis [5, 6].

Key features:

• A potent and specific Syk inhibitor
• Each lot is highly pure (≥97%) and functionally tested

Read our review on the C-Type Lectin Receptors.

References:

1. Braselmann S. et al., 2006. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 319(3):998-1008.
2. Honjoh C. et al., 2017.Association of C-Type Lectin Mincle with FcεRIβγ Subunits Leads to Functional Activation of RBL-2H3 Cells through Syk. Sci Rep. 7:46064.
3. Kimura Y. et al., 2014.Dectin-1-mediated signaling leads to characteristic gene expressions and cytokine secretion via spleen tyrosine kinase (Syk) in rat mast cells. J Biol Chem. 289(45):31565-75.
4. Gross O. et al., 2009.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433-436.
5. Chen L. et al., 2008.SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood. 111(4):2230-7.
6. Zhang J. et al., 2012.A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 481(7381):329-34.