R406

Syk inhibitor

Inhibition of Syk signaling by R406

R406 besylate (also known as Tamatinib besylate) is an R406 salt. R406 is the active metabolite of Fostamatinib. It was initially identified as a potent inhibitor of the spleen tyrosine kinase (Syk). R406 binds to the ATP binding pocket of Syk and inhibits its kinase activity as an ATP-competitive inhibitor [1].

 More details

R406 has also been cited as an inhibitor of the Flt-3 and Ret tyrosine kinases [2]. Because Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation, it is considered a good target for the inhibition of various autoimmune conditions, including rheumatoid arthritis and lymphoma. R406 was shown to attenuate autoantibody-induced arthritis in mice [1]. and to induce significant apoptosis in cancers displaying Syk over-expression [3, 4]. Interestingly, R406 selectively abrogates Syk-dependent NLRP3 inflammasome activation by C. albicans but not by the bacterial toxin nigericin [5].

Key features:

• 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. Jakuz Z. et al., 2010. Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. Arthritis Rheum. 62(7):1889.
3. 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.
4. Zhang J. et al., 2012. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 481(7381):329.
5. Gross O. et al., 2009. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433.
6. Mócsai A. et al., 2010. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 10(6):387.

Figures

R406 inhibits Syk signaling in a dose-dependent manner. HEK-Blue™ hDectin-1b cells were incubated in the presence of increasing concentrations of R406 and the Dectin-1 agonist WGP Dispersible (100 μg/ml). After overnight incubation, the inhibitory activity of R406 on Dectin-1-induced Syk/CARD9 signaling was assessed by measuring the levels of SEAP using QUANTI‑Blue™ Solution. Data are shown as percentage (%) of inhibition.

Specifications

CAS number: 841290-81-1

Chemical Name: 2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-, benzenesulfonate (1:1)

Formula: C₂₈H₂₉FN₆O₈S

Molecular weight: 628.63 g/mol

Solubility: 20 mg/ml in DMSO

Purity: ≥97% (UHPLC)

Quality control:

• The absence of bacterial contamination (e.g. lipoproteins and endotoxins) has been confirmed using HEK-Blue™ TLR2 and HEK-Blue™ TLR4 cells.

Contents

R406* (R406 besylate) is provided as a lyophilized powder. It is available in two quantities:

• inh-r406n: 2 mg
• inh-r406n-5: 5 x 2 mg 

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 the 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 the 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 besylate: