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    G-749
    G-749

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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 #: V0588
    CAS #: 1457983-28-6Purity ≥98%

    Description: G-749 (G749) is a novel and potent FLT3 inhibitor with potential antineoplastic activity. It inhibits FLT3 (WT), FLT3 (D835Y), and Mer with IC50s of 0.4 nM, 0.6 nM and 1 nM, respectively. G-749 demonstrates high anti-proliferative activity in vitro and in vivo antitumor efficacy as well. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. 

    References: Blood. 2014 Apr 3;123(14):2209-19.

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    Molecular Weight (MW)521.41
    FormulaC25H25BrN6O2
    CAS No.1457983-28-6
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 24 mg/mL (46.02 mM)
    Water:<1 mg/mL
    Ethanol:<1 mg/mL
    Other info

    Chemical Name: 8-bromo-2-((1-methylpiperidin-4-yl)amino)-4-((4-phenoxyphenyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one

    InChi Key: SXWMIXPJPNCXQQ-UHFFFAOYSA-N

    InChi Code: InChI=1S/C25H25BrN6O2/c1-32-13-11-17(12-14-32)29-25-30-22-20(26)15-27-24(33)21(22)23(31-25)28-16-7-9-19(10-8-16)34-18-5-3-2-4-6-18/h2-10,15,17H,11-14H2,1H3,(H,27,33)(H2,28,29,30,31)

    SMILES Code: O=C1NC=C(Br)C2=NC(NC3CCN(C)CC3)=NC(NC4=CC=C(OC5=CC=CC=C5)C=C4)=C21

    Synonyms

    G-749; G 749; G749


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    In Vitro

    In vitro activity: In FLT3-WT-bearing RS4-11 cells and FLT3-ITD-harboring MV4-11 and Molm-14 cells, G-749 potently inhibits autophosphorylation of FLT3 with IC50 of ≤8 nM. In leukemia cells, G-749 shows antiproliferative activity by inducing apoptosis. In BaF3 cell lines that stably express FLT3-ITD/N676D, FLT3-ITD/F691L, FLT3-D835Y, or FLT3-D835Y/N676D, G-749 shows strong inhibitory activity with IC50 of<10 nM, and thus overcomes drug resistance. In blasts of AML patients, G-749 also exhibits potent antileukemia activity.


    Kinase Assay: Activity assays are conducted using Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology from Perkin-Elmer. Briefly, 10 ng/mL FLT3 enzyme, a serial diluted G-749, 80 nM substrate of ULight-poly-GT peptide and variable amounts of ATP (8.5 µM to 1088 μM) are mixed in kinase assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT and 0.01% Tween-20) and are added to a 384-well OptiPlate-384 in a volume of 10 μL. Kinase reactions are incubated at room temperature for up to 1 h and then stopped by the addition of 5 μL of 10 mM EDTA. A volume of 5 μL of the specific Eu-labeled-anti-phosphopeptide antibody diluted in LANCE Detection Buffer is then added to a final concentration of 2 nM. After 30-minute incubation, assay plates are incubated at 23°C and the LANCE signal is measured on an EnVision Multilabel Reader. Excitation wavelength is set at 320 nm and emission monitored at 615 nm (donor) and 665 nm (acceptor). The IC50 is calculated using nonlinear regression analysis analysis by GradPad Prism 5. 


    Cell Assay: Cells (MV4-11, RS4-11, K562, HEL, and Molm-14 cells) are seeded at a density of 2 ×104 cells per well and treated with the indicated concentrations of test inhibitor for 72 hours at 37℃. The conditioned medium (CM) is prepared from HS-5 cell culture for 5 days under routine culture conditions, clarified by centrifugation, and used immediately. The CM is added to complete medium at a final concentration of 35%. In coculture experiments, 5 ×104 AML blast cells are plated in 24-well plates containing 1 ×104 HS-5 monolayers and then cultured for at least 48 hours before the exposure of inhibitors. Cell viability is determined by an ATPLite assay.

    In VivoIn MV4-11 xenograft mice, G-749 (30 mg/kg p.o.) effectively inhibits the FLT3 pathway and significant inhibits tumor growth. In an orthogonal model of bone marrow engraftment using Molm-14 cells, G-749 (20 mg/kg p.o.) also inhibits tumor growth and increases survival.
    Animal modelMV4-11 xenograft mouse model and Molm-14 orthogonal mouse model
    Formulation & DosageDissolved in 20% hydroxypropyl -β-cyclodextrin (HPBCD); 30 mg/kg; Oral gavage
    References

    Blood. 2014 Apr 3;123(14):2209-19.


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

    G-749

    In vivo antitumor activity of G-749 in xenograft and engrafted mouse model. Blood. 2014 Apr 3; 123(14): 2209–2219.

    G-749

    Potent inhibition of G-749 in AML patient plasma milieu. Blood. 2014 Apr 3;123(14):2209-19.

    G-749

    Potent inhibition of G-749 against patient blasts harboring FLT3-ITD or FLT3-D835Y. Blood. 2014 Apr 3;123(14):2209-19.


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