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    TPCA-1
    TPCA-1

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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 #: V0751
    CAS #: 507475-17-4Purity ≥98%

    Description: TPCA-1 (also known as GW683965) is novel, potent, and selective inhibitor of IKK-2 with IC50 of 17.9 nM in a cell-free assay, it exhibits 22-fold selectivity over IKK-1. 

    References: J Pharmacol Exp Ther. 2005 Jan;312(1):373-81; J Interferon Cytokine Res. 2012 Aug;32(8):368-77.

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    Molecular Weight (MW)279.29
    FormulaC12H10FN3O2S
    CAS No.507475-17-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 56 mg/mL (200.5 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% Cremophor EL, 2% N,N-dimethylacetamide: 15 mg/mL  
    SynonymsGW683965; TPCA-1; GW-683965; TPCA1; TPCA 1; GW 683965 

    Chemical Name: 5-(4-fluorophenyl)-2-ureidothiophene-3-carboxamide

    InChi Key: SAYGKHKXGCPTLX-UHFFFAOYSA-N

    InChi Code: InChI=1S/C12H10FN3O2S/c13-7-3-1-6(2-4-7)9-5-8(10(14)17)11(19-9)16-12(15)18/h1-5H,(H2,14,17)(H3,15,16,18)

    SMILES Code: O=C(C1=C(NC(N)=O)SC(C2=CC=C(F)C=C2)=C1)N


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    In Vitro

    In vitro activity: In a time-resolved fluorescence resonance energy transfer assay, TPCA-1 inhibits human IKK-2 activity with an IC50 of 17.9 nM. In addition, TPCA-1 is demonstrated to be ATP-competitive. Besides, TPCA-1 exhibits IC50 values of 400 nM and 3600 nM against IKK-1 and JNK3, respectively. TPCA-1 inhibits the production of TNF-α, IL-6, and IL-8 in a concentration-dependent manner, exhibiting IC50 values of 170, 290, and 320 nM, respectively. TPCA-1 inhibits glioma cell proliferation, as well as TNF-induced RelA (p65) nuclear translocation and NFκB-dependent IL8 gene expression. Importantly, TPCA-1 inhibits IFN-induced gene expression, completely suppressing MX1 and GBP1 gene expression, while having only a minor effect on ISG15 expression.


    Kinase Assay: Recombinant human IKK-2 (residues 1-756) is expressed in baculovirus as an N-terminal GST-tagged fusion protein, and its activity is assessed using a time-resolved fluorescence resonance energy transfer assay. In brief, IKK-2 (5 nM final) diluted in assay buffer (50 mM HEPES, 10 mM MgCl2, 1 mM CHAPS, pH 7.4, with 1 mM DTT and 0.01% w/v BSA) is added to wells containing various concentrations of compound or dimethyl sulfoxide (DMSO) vehicle (3% final). The reaction is initiated by the addition of GST-IκBα substrate (25 nM final)/ATP (1 μM final), in a total volume of 30 μL. The reaction is incubated for 30 min at room temperature, then terminated by the addition of 15 μL of 50 mM EDTA. Detection reagent (15 μL) in buffer (100 mM HEPES, pH 7.4, 150 mM NaCl, and 0.1% w/v BSA) containing antiphosphoserine- IκBα-32/36 monoclonal antibody 12C2, labeled with W-1024 europium chelate, and an allophycocyanin-labeled anti-GST antibody is added, and the reaction is further incubated for 60 min at room temperature. The degree of phosphorylation of GST- IκBαis measured as a ratio of specific 665-nm energy transfer signal to reference europium 620-nm signal, using a Packard Discovery plate reader. 


    Cell Assay: Ten microliters of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) from stock solution (10 mg/mL) is added to each well of 96-well plates containing glioma cells and incubated at 37 °C for 2–4 h. Oxidized MTT is solubilized by adding 100 μL of 10% sodium dodecyl sulfate (SDS) in 0.01 N HCL, and plates are incubated at 37 °C for 4 h in a humidified chamber. Plates are read at 570 nm on a plate reader.

    In VivoProphylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., results in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. are comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1beta, IL-6, TNF-alpha, and interferon-gamma, is significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo results in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduces the severity of CIA, as does etanercept administration at 12.5 mg/kg, i.p., every other day.
    Animal modelMurine collagen-induced arthritis
    Formulation & DosageDissolved in 0.9% DMSO, 7% dimethylacetoacetamide (DMA), and 10% Cremophor El; 3, 10, or 20 mg/kg; i.p. injection
    References

    J Pharmacol Exp Ther. 2005 Jan;312(1):373-81; J Interferon Cytokine Res. 2012 Aug;32(8):368-77.


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

    TPCA-1

    BMS-345541 and TPCA-1 attenuate IFN-induced antiviral state against VSV and EMCV in Glioma cells. J Interferon Cytokine Res. 2012 Aug;32(8):368-77.

    TPCA-1

    BMS-345541 and TPCA-1 inhibit glioma cell proliferation, NFκB activation, and NFκB-regulated IL8 gene expression. J Interferon Cytokine Res. 2012 Aug;32(8):368-77.
     

    TPCA-1

    BMS-345541 and TPCA-1 attenuate IFN-induced ISG expression. J Interferon Cytokine Res. 2012 Aug;32(8):368-77.

    TPCA-1

    BMS-345541 does not affect STAT1 and STAT2 activation. J Interferon Cytokine Res. 2012 Aug;32(8):368-77.

    TPCA-1

    BMS-345541 blocks IFN protection against VSV-induced cytopathic effect in glioma cells. J Interferon Cytokine Res. 2012 Aug;32(8):368-77.
     

    TPCA-1

    BMS-345541 blocks IFN protection against EMCV-induced cytopathic effect in glioma cells. J Interferon Cytokine Res. 2012 Aug;32(8):368-77.


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