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    Tamatinib besylate (R406)
    Tamatinib besylate (R406)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0583
    CAS #: 841290-81-1Purity ≥98%

    Description: Tamatinib besylate (formerly R-406 besylate; prodrug of R 406) is a novel, potent and ATP-competitive inhibitor of spleen tyrosine kinase/Syk with potential anti-inflammatory activity. It inhibits Syk with IC50 of 41 nM in cell-free assays. Syk plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). Tamatinib strongly inhibits Syk but not Lyn, and is 5-fold less potent against Flt3. It has the potential to be used for treatment of the inflammation associated with bronchial asthma resulting from allergen-induced airway hyperresponsiveness (AHR), rheumatoid arthritis and other autoimmune conditions.

    References: J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008; Blood. 2009 Jul 30;114(5):1029-37.

    Related CAS #: 841290-80-0 (free base); 841290-81-1 (besylate) 

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    Molecular Weight (MW)628.63
    FormulaC22H23FN6O5.C6H6O3S
    CAS No.841290-81-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 126 mg/mL (200.4 mM)
    Water: <1 mg/mL
    Ethanol: 8 mg/mL (12.7 mM)
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% Propylene glycol: 30 mg/mL
    Synonyms

    Synonym: R406 benzenesulfonate; R-406 benzenesulfonate; R-406 besylate; R406; R-406; R 406; R 406 besylate; R406 besylate; R406 benzenesulfonate; Tamatinib,

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

    InChi Key: UXDRJPYSTZHIOE-UHFFFAOYSA-N

    InChi Code: InChI=1S/C22H23FN6O5.C6H6O3S/c1-22(2)20(30)28-19-13(34-22)6-7-16(27-19)26-18-12(23)10-24-21(29-18)25-11-8-14(31-3)17(33-5)15(9-11)32-4;7-10(8,9)6-4-2-1-3-5-6/h6-10H,1-5H3,(H3,24,25,26,27,28,29,30);1-5H,(H,7,8,9)

    SMILES Code: CC1(C(=O)NC2=C(O1)C=CC(=N2)NC3=NC(=NC=C3F)NC4=CC(=C(C(=C4)OC)OC)OC)C.C1=CC=C(C=C1)S(=O)(=O)O


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    In Vitro

    In vitro activity: R406 is an ATP-competitive inhibitor of Syk with a Ki value of 30 nM. R406 selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells. R406 inhibits cellular proliferation of a large panel of diffuse large B-cell lymphoma (DLBCL) cell lines at EC50 values ranging from 0.8 μM to 8.1 μM. R406 treatment (1 μM or 4 μM) induces the activation of caspases 9 and 3, but not caspase 8, leading to significant apoptosis of the majority of DLBCL cell lines. Pretreatment of R406 completely blocks the phosphorylation of SYK525/526 and the SYK-dependent phosphorylation of BLNK in R406-sensitive DLBCLs following B-cell receptor (BCR) crosslinking. R406 potently decreases MMP-9 mRNA levels by 2.8- and 4.3-fold lower than controls after 24 and 48 hours treatment, respectively, and reduces the invasive capacity of the RL cells.


    Kinase Assay: R406 is serially diluted in DMSO and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated BGG). ATP and substrate in kinase buffer are added at room temperature, resulting in a final DMSO concentration on 0.2%. The kinase reactions are performed in a final volume of 20 μL containing 5 μM HS1 peptide substrate and 4 μM ATP and started by addition of 0.125 ng of Syk in kinase buffer. The reaction is allowed to proceed for 40 minutes at room temperature. The reaction is stopped by the addition of 20 μL of PTK quench mix containing EDTA/anti-phosphotyrosine antibody (1X final)/fluorescent phosphopeptide tracer (0.5X final) diluted in FP Dilution Buffer. The plate is incubated for 30 minutes in the dark at room temperature and then read on a Polarion fluorescence polarization plate reader. Data are converted to amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit. For IC50 determination, R406 is tested at eleven concentrations in duplicate and curve-fitting is performed by non-linear regression analysis using Prism GraphPad Software. 


    Cell Assay: DLBCL cell lines are treated with serial dilutions of R406 (0.3, 0.6, 1.25, 2.5, or 5 μM) for 72 or 96 hours. Thereafter, cellular proliferation is determined by MTT assay, and cell apoptosis is assessed by using annexin V–FITC/propidium iodide (PI) staining. For the determination of caspase 9, 8, and 3, cells are lysed, size-fractionated by polyacrylamide gel electrophoresis (PAGE), and immunoblotted.

    In VivoR406 has shown efficacy in a number of animal models of immune disorders. Oral administration of R406 in mice with immune complex-mediated inflammation significantly inhibits the cutaneous reverse passive Arthus reaction by approximately 72% and 86% at 1 mg/kg and 5 mg/kg, respectively, compared with the control. R406 treatment at 10 mg/kg significantly reduces inflammation and swelling, decreases the progressive arthritis to a lower level in the passive anticollagen antibody-challenged mice, and delays the onset and reduces paw thickening and clinical arthritis by approximately 50% in the K/BxN serum transfer mice model.
    Animal modelFemale C57BL/6 mice challenged intravenously with 1% ovalbumin (OVA) in saline (10 mg/kg) containing 1% Evans blue dye, female Balb/c mice with the anticollagen antibody-induced arthritis, and female C57BL/6 mice with arthritis induced by intraperitoneal
    Formulation & DosageFormulated in DMSO and diluted in saline containing 35% TPGS, 60% PEG 400, and 5% propylene glycol; 10 mg/kg;  Oral gavage
    References

    J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008; Blood. 2008 Feb 15;111(4):2230-7. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    R406

    R406

    R406

    The Syk inhibitor R406 induces CLL cell apoptosis and abrogates BCR-derived survival signals. Blood. 2009 Jul 30; 114(5): 1029–1037.


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