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    Tozasertib (VX680; MK0457)
    Tozasertib (VX680; MK0457)

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    This product is for research use only, not for human use. We do not sell to patients.
    Number: - + Pieces(InventoryPieces)
    InvivoChem Cat #: V0344
    CAS #: 639089-54-6Purity ≥98%

    Description: Tozasertib (formerly VX-680; MK-0457) is a novel and potent pan-Aurora kinase (AK) inhibitor with potential anticancer activity. It inhibits Aurora kinase A (AKA) with a Kiapp of 0.6 nM in a cell-free assay, and is less potent towards Aurora B/Aurora C. It shows 100-fold higher selectivity for Aurora A over 55 other kinases with Kis of 0.6, 18, 4.6 nM for Aurora B/C kinases, respectively. Tozasertib exhibited potent in vitro antiproliferative activity and high in vivo antitumor efficacy. VX680 was discovered through a molecular screening campaign and is a potent inhibitor of pan-aurora kinase as well as other kinases including Src, GSK3β, Flt3, JAK2, BCR-Abl (wild type) and BCR-Abl (T315I mutant). It binds to the inactive conformations of non-aurora kinases preventing activation, which leads to the inhibition of a wide array of kinases.

    References: Cancer Res. 2006 Jan 15;66(2):1007-14; Endocr Relat Cancer. 2008 Jun;15(2):559-68; Nat Med. 2004 Mar;10(3):262-7.

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    Molecular Weight (MW)464.59
    CAS No.639089-54-6
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 93 mg/mL (200.2 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL

    Tozasertib, MK-0457; VX-680; MK 0457; MK-0457; VX680; VX 680; MK0457; VE 465; VE465; VE-465

    Chemical Name: (N-[4({4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5 -yl)amino]pyrimidin-2-yl}thio)phenyl]cyclopropanecarboxamide)


    InChi Code: InChI=1S/C23H28N8OS/c1-15-13-20(29-28-15)25-19-14-21(31-11-9-30(2)10-12-31)27-23(26-19)33-18-7-5-17(6-8-18)24-22(32)16-3-4-16/h5-8,13-14,16H,3-4,9-12H2,1-2H3,(H,24,32)(H2,25,26,27,28,29)

    SMILES Code: O=C(C1CC1)NC2=CC=C(SC3=NC(NC4=CC(C)=NN4)=CC(N5CCN(C)CC5)=N3)C=C2 

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    In Vitro

    In vitro activity: Although its multi-kinase profile, VX-680 induces similar cytotoxicity with IC50 of approximately 300 nM and exhibits an AUR B-like inhibitory phenotype of G2/M arrest, endoreduplication and apoptosis in BaF3 cells transfected with ABL or FLT-3 (mutant and wild type) kinases. VX-680 prevents the CAL-62 proliferation in a time-dependent manner. VX-680 treatment for 14 days significantly decreases the number and size of colonies by approximately 70% in the 8305C and 90% in the CAL-62, 8505C and BHT-101. Treatment of the different ATC cells with VX-680 inhibits proliferation with the IC50 between 25 and 150  nM. The VX-680 significantly impairs the ability of the different cell lines to form colonies in soft agar. Analysis of caspase-3 activity indicates that VX-680 induces apoptosis in the different cell lines. CAL-62 cells exposed for 12  hours to VX-680 showed an accumulation of cells with ≥4N DNA content. Time-lapse analysis demonstrates that VX-680-treated CAL-62 cells exit metaphase without dividing. Moreover, histone H3 phosphorylation is abrogated following VX-680 treatment. VX-680 has significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples

    Kinase Assay: The consumption of ATP is coupled via the pyruvate kinase/lactic dehydrogenase enzyme pair to the oxidation of NADH, which can be monitored through the decrease in absorption at 340 nm. Reactions contains 100 mM Tris (pH 8), 10 mM MgCl2, 2.2 mM ATP, 1 mM phosphoenolpyruvate, 0.6 mg/mL NADH, 75 units/mL pyruvate kinase, 105 units/mL lactate dehydrogenase, and 0.5 mM substrate peptide (sequence: EAIYAAPFAKKK). Reactions (75 μL) are started by adding sufficient kinase to bring the reactions to 30 nM kinase concentration and the decrease in absorbance is monitored over 30 minutes at 30°C in a microtiter plate spectrophotometer. Inhibitory constants are obtained through addition of 3.75 μL VX-680 in 100% DMSO or DMSO alone. Ki values are calculated as follows, K i = IC50 / (1 + [S]/Kd), where [S] = [ATP] = 2.2 mM, and Kd (of ATP to Abl) = 70 μM. These values are calculated assuming a Kd (ATP) of 70 μM for wild type and H396P Abl kinase domain.

    Cell Assay: The CAL-62 cells are cultured in the absence (dimethyl sulfoxide, DMSO) or the presence of 500  nM VX-680 for different periods of time (1-5 days). The dose-dependent effects of VX-680 on cell proliferation are evaluated by treating the different ATC cells for 4 days with different concentrations of the Aurora inhibitor (5–500  nM). The cells are pulse labeled with 30  mM BrdU for 2  hours before the end of the incubation time. The BrdU incorporation is analyzed by means of a colorimetric immunoassay using the cell proliferation ELISA kit. The results from VX-680-treated cells are compared with those observed in control cells and expressed as a fold of variation versus control.

    In VivoVX-680 gives rise to a marked decrease in tumor size in a human AML (HL-60) xenograft model. In mude mice treateed with VX-680 at 75 mg/kg, twice a day intraperitoneally (b.i.d. i.p.) for 13 days, mean tumor volumes are reduced by 98%. Tumor growth decrease is dose dependent and significant at a dose of 12.5 mg/kg b.i.d. VX-680 is well tolerated, with a small decrease in body weight observed only at the highest dose. VX-680 also triggers tumor regresson in pancreatic and colon xenograft models. VX-680 also displays potent antitumor activity when infused i.v. in mude rats bearing established HCT116 tumors. A higher dose of VX-680 (2 mg/kg/h) improves efficacy with a 56% decrease in mean tumor volume.
    Animal modelFemale athymic NCr-nu mice bearing HL-60 leukemia cells
    Formulation & DosageDissolved in 50% PEG300 in 50 mM phosphate buffer; 50, 75 mg/kg;  i.p. injection

    Cancer Res. 2006 Jan 15;66(2):1007-14; Endocr Relat Cancer. 2008 Jun;15(2):559-68; Nat Med. 2004 Mar;10(3):262-7.

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

    VX-680 (Tozasertib, MK-0457)

    ABL2 bound to a type I inhibitor 2. (A) ABL2:2, showing the compound bound to the ATP binding site, and the ordered activation loop. Compound 2 is shown in yellow.   2011 Apr 14;54(7):2359-67.

    VX-680 (Tozasertib, MK-0457)

    Myristate binding pocket of ABL2. (A) Surface of the myristate binding pocket of ABL2, with imatinib shown as a yellow ball-and-stick representation.  2011 Apr 14;54(7):2359-67.

    VX-680 (Tozasertib, MK-0457)

    Comparison of ABL2:imatinib and ABL2:1 with ABL1:imatinib and ABL1:1.  2011 Apr 14;54(7):2359-67.


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