R406

Syk inhibitor

Inhibition of Syk signaling by R406

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. 

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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 the 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
• InvitroFit™: each lot is highly pure (≥97%) and functionally tested

Read our review on the C-Type Lectin Receptors.

See our Poster on Inhibitor Signaling Pathways

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.

Figures

R406 inhibits the Dectin-1 response in a dose-dependent manner.
HEK-Blue™ hDectin-1b cells were stimulated with the dectin-1 agonist HKSC (107 cells/ml; heat killed Saccharomyces cerevisiae) and increasing concentrations of R406. After overnight incubation, R406‑induced inhibition of Dectin-1-Syk/CARD9 signaling was assessed by measuring the levels of SEAP using QUANTI‑Blue™ Solution. The optical density (OD) at 630 nm is shown as mean ± SEM.

Specifications

CAS number: 841290-80-0

Chemical Name: 6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino) pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

Formula: C₂₂H₂₃FN₆O₅

Molecular weight: 470.45 g/mol

Solubility: 10 mg/ml (21 mM) in DMSO

Purity: ≥97% (UHPLC)

Quality control:

• The inhibitory activity has been confirmed using cellular assays with HEK-Blue™ hDectin-1b Cells.
• The absence of bacterial contamination (e.g. lipoproteins and endotoxins) has been confirmed using HEK-Blue™ TLR2 and HEK-Blue™ TLR4 cells.

Contents

• 2 mg of R406 provided as a lyophilized powder

R406 is shipped at room temperature.

 Upon receipt, store at -20°C.

Details

Spleen tyrosine kinase

Spleen tyrosine kinase (Syk) is a tyrosine kinase that has long been associated with the adaptive immune response, in particular with signaling by B cell receptors (BCRs) and Fc receptors (FcRs). More recently, it has been linked with innate immunity [1]. Specifically, Syk participates in innate recognition of fungal and other microbial pathogens by C-type lectins, namely Dectin-1, Dectin-2, and Mincle (Macrophage-inducible C-type lectin).
Syk activation by C-type lectins activates the caspase-recruitment domain 9–B cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma translocation protein 1 (CARD9–BCL-10–MALT1) pathway. Syk is also required for NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation following fungal infection.

1. Mócsai A. et al., 2010. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol . 10(6):387-402.

Chemical structure of R406: