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    NVP-BVU972
    NVP-BVU972

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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 #: V0597
    CAS #: 1185763-69-2Purity ≥98%

    Description: NVP-BVU972 (also names as BVN972; BVN-972) is a novel c-Met inhibitor with potential anticancer activity. It inhibits c-Met with an IC50 of 14 nM. It exhibits excellent anti-proliferative activity in vitro against various cancer cells such as EBC-1, GTL-16, and MKN-45 with IC50 values of 82, 66 and 32 nM, respectively.  

    References: Cancer Res. 2011 Aug 1;71(15):5255-64.

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    Molecular Weight (MW)340.38
    FormulaC20H16N6
    CAS No.1185763-69-2
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 68 mg/mL (199.8 mM)
    Water: <1 mg/mL
    Ethanol: 68 mg/mL (199.8 mM)
    Other infoChemical Name: 6-[[6-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]methyl]quinoline
    InChi Key: RNCNPRCUHHDYPC-UHFFFAOYSA-N
    InChi Code: InChI=1S/C20H16N6/c1-25-13-16(11-23-25)19-6-7-20-22-12-17(26(20)24-19)10-14-4-5-18-15(9-14)3-2-8-21-18/h2-9,11-13H,10H2,1H3
    SMILES Code: CN1N=CC(C2=NN3C(C=C2)=NC=C3CC4=CC=C5N=CC=CC5=C4)=C1
    Synonyms NVP-BVU-972; BVU-972; NVP-BVU972; NVP-BVU 972; BVU 972; BVU972.


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    In Vitro

    In vitro activity: NVP-BVU972 potently inhibits MET kinase but displays low inhibition against other kinases including the most closely related kinase RON with IC50 values of more than 1000 nM. NVP-BVU972 also suppresses constitutive MET phosphorylation in GTL-16 cells or HGF-stimulated MET phosphorylation in A549 cells with IC50 values of 7.3 nM and 22 nM, respectively. NVP-BVU972 potently prevents the growth of the MET gene amplified cell lines GTL-16, MKN-45 and EBC-1 with IC50 values of 66 nM, 82 nM and 32 nM, respectively. In line with their high frequency in the NVP-BVU972 screen, Y1230 and D1228 mutations give rise to dramatic shifts in the measured IC50 values for NVP-BVU972 in BaF3 cell line. Resistance triggered by V1155L is more limited to NVP-BVU972. A dose-dependent reduction in TPR-MET phosphorylation when applying NVP-BVU972 to BaF3 cells expressing wild-type TPR-MET. Both Y1230H and D1228A mutations abrogated the effect of NVP-BVU972 but not AMG 458. However, F1200I and L1195V interferes with the potency of NVP-BVU972 to prevent TPR-MET phosphorylation.


    Kinase Assay: Enzyme activity is measured in a time resolved fluorescence resonance energy transfer (TR-FRET) assay, detecting tyrosine phosphorylation with a Eu-labelled anti-phospho-tyrosine antibody (fluorescence donor) and Allophycocyanin conjugated to Streptavidin (fluorescence acceptor) which binds to a biotin on the substrate peptide. For each variant, Km concentrations for ATP are determined in the absence of NVP-BVU972, and the ATP concentration in the kinase reaction is set to Km (4 μM for MET wt, 1 μM for MET Y1230H and MET F1200I). NVP-BVU972 is dissolved and diluted in DMSO and assayed in quadruplicate. Kinase reactions are carried out in 50 mM Tris-HCl pH 7.5, 8 mM MgCl2, 4 mM MnCl2, 0.05 % Tween 20, 0.05% bovine serum albumin, 0.1 mM EDTA, 1 mM DTT, 0.1 mM Na3VO4, in white 1536 well plates at room temperature. NVP-BVU972 and enzyme are incubated in a volume of 2 μL for 20 min, followed by the addition of 1 μL ATP and 1 μL biotinylated peptide substrate (PTK1) to final concentrations of Km and 1 μM, respectively. Enzyme concentrations in the reactions are 5 nM for MET wt, and 4 nM for the F1200I and Y1230H variants. After 90 min, reactions are stopped by addition of 1 μL stop/detection solution to reach final concentrations of 10 mM EDTA, 3.5 nM Eu-labelled antiphospho-tyrosine antibody PY20, and 10 nM Streptavidin Allophycocyanin. Time resolved fluorescence resonance energy transfer is measured in an Envision plate reader (excitation 320 nm, emission 615 nm and 665 nm).


    Cell Assay:  BaF3 cells containing TPR-MET or various mutants thereof are grown in RPMI 1640 medium containing 10% fetal calf serum. For maintenance of parental BaF3 cells the medium is additionally supplemented with 10 ng/mL interleukin-3 (IL-3). For proliferation assays, BaF3 cells are seeded on 96-well-plates in triplicates at 104 cells per well and incubated with various concentrations of NVP-BVU972 for 72 hours followed by quantification of viable cells using a resazurin sodium salt dye reduction readout. IC50 values are determined with the XLFit Excel Add-In using a 4-parameter dose response model.

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    References

    Cancer Res. 2011 Aug 1;71(15):5255-64.


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

    NVP-BVU972

    Resistance profile of the MET inhibitor NVP-BVU972. Cancer Res. 2011 Aug 1;71(15):5255-64.

    NVP-BVU972

    A, resistance profile of AMG 458. B, model of AMG 458 bound to the MET kinase domain on the basis of the reported crystal structure of MET in complex with a “type II” pyrrolopyridine-pyridone inhibitor of similar chemical structure (PDB code: 3CE3). Cancer Res. 2011 Aug 1;71(15):5255-64.

    NVP-BVU972

    Functional characterization of resistance mutations. Cancer Res. 2011 Aug 1;71(15):5255-64.


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