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    Bosutinib (SKI-606; Bosulif)
    Bosutinib (SKI-606; Bosulif)

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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 #: V0665
    CAS #: 380843-75-4Purity ≥98%

    Description: Bosutinib (formerly also known as SKI-606; trade name Bosulif) is a novel, quinolone-based, anpotent dual Src/Abl kinase inhibitor with potential antitumor activity. It inhibits Src and Abl with IC50 of 1.2 nM and 1 nM in cell-free assays, respectively. Bosutinib was approved by the US FDA and EU European Medicines Agency on September 4, 2012 and 27 March 2013 respectively for treating Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients.

    References: Cancer Res. 2003 Jan 15;63(2):375-81; J Med Chem. 2001 Nov 8;44(23):3965-77.


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    Molecular Weight (MW)530.45
    FormulaC26H29Cl2N5O3
    CAS No.380843-75-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (188.5 mM)
    Water: <1 mg/mL
    Ethanol: 2 mg/mL (3.8 mM)
    Solubility (In vivo)2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10 mg/mL
    Synonyms

    Synonym: Bosutinib; SKI606; SKI 606; SK-I606; trade name: Bosulif.

    Chemical Name: 4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

    InChi Key: UBPYILGKFZZVDX-UHFFFAOYSA-N

    InChi Code: InChI=1S/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)

    SMILES Code: N#CC1=C(NC2=CC(OC)=C(Cl)C=C2Cl)C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=C1


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    In Vitro

    In vitro activity: Bosutinib is selective for Src over non-Src family kinases with an IC50 of 1.2 nM, and potently inhibits Src-dependent cell proliferation with an IC50 of 100 nM. Bosutinib significantly inhibits the proliferation of Bcr-Abl-positive leukemia cell lines KU812, K562, and MEG-01 but not Molt-4, HL-60, Ramos, and other leukemia cell lines, with IC50 of 5 nM, 20 nM and 20 nM, respectively, more potently than that of STI-571. Similar to STI-571, Bosutinib displays antiproliferative activity against the Abl-MLV-transformed fibroblasts with IC50 of 90 nM. Bosutinib ablates tyrosine phosphorylation of Bcr-Abl and STAT5 in CML cells and of v-Abl expressed in fibroblasts at the concentration of ~50 nM, 10-25 nM and 200 nM, respectively, leading to the Bcr-Abl downstream signaling inhibition of Lyn/Hck phosphorylation. Although unable to inhibit the proliferation and survival of breast cancer cells, Bosutinib significantly decreases the motility and invasion of breast cancer cells with IC50 of ~250 nM, involved with an increase in cell-to-cell adhesion and membrane localization of β-catenin.


    Kinase Assay: The Src kinase activity is measured in an ELISA format. Src (3 units/reaction), reaction buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 0.1 mM EGTA, 0.5 mM Na3VO4) and cdc2 substrate peptide are added to various concentration of Bosutinib and incubated at 30 °C for 10 minutes. The reaction is started by the addition of ATP to a final concentration of 100 μM, incubated at 30 °C for 1 hour and stopped by addition of EDTA. Instructions from the manufacturer are followed for subsequent steps. The Abl kinase assay is performed in a DELFIA solid phase europium-based detection assay format. Biotinylated peptide (2 μM) is bound to streptavidin-coated microtitration plates for 1.5 hours in 1 mg/mL ovalbumin in PBS. The plates are washed for 1 hour with PBS/0.1% Tween 80, followed by a PBS wash. The kinase reaction is incubated for 1 hour at 30°C. Abl kinase (10 units) is mixed with 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 80 μM EGTA, 100 μM ATP, 0.5 mM Na3VO4, 1% DMSO, 1 mM HEPES (pH 7.0), 200 μg/mL ovalbumin and various concentration of Bosutinib. The reaction is stopped with EDTA at a final concentration of 50 mM. The reaction is monitored with Eu-labeled phosphotyrosine antibody and DELFIA enhancement solution.


    Cell Assay: Cells ( Abl-MLV, Rat 2, KU812, K562, and MEG-01 cells) are exposed to various concentrations of Bosutinib for 72 hours. Anchorage-independent proliferation of Abl-MLV-transformed fibroblasts is measured in 96-well ultra-low binding plates treated with Sigmacote to block residual cell attachment. Cell proliferation is measured with MTS or Cell-Glo. For the determination of cell cycle or cell death, cells are prepared for FACS analysis in the CycleTest Plus DNA reagent kit and analyzed on a fluorescence-activated cell sorter flow cytometer.

    In VivoBosutinib (60 mg/kg/day) is active against Src-transformed fibroblasts xenografts and HT29 xenografts in nude mice with T/C of 18% and 30%, respectively. Oral administration of Bosutinib for 5 days significantly suppresses K562 tumor growth in mice in a dose-dependent manner, with the large tumors eradicated at dose of 100 mg/kg and tumor free at 150 mg/kg without overt toxicity. As being inactive against Colo205 xenografts in nude mice at 50 mg/kg twice daily, Bosutinib dosing at 75 mg/kg twice daily is necessary against Colo205 xenografts, and increasing the dose of Bosutinib has no additional benefit, in contrast to the significant dose-dependent ability against HT29 xenografts.
    Animal modelFemale nude  mice injected with K562 cells
    Formulation & DosageSuspended in 0.5% methocel/0.4% Tween 80; 150 mg/kg; Oral gavage
    References

    Cancer Res. 2003 Jan 15;63(2):375-81; J Med Chem. 2001 Nov 8;44(23):3965-77.


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

    Bosutinib (SKI-606)

    SKI-606 is a potent inhibitor of CML cell proliferation and survival. Cancer Res. 2003 Jan 15;63(2):375-81.

    Bosutinib (SKI-606)

    SKI-606 inhibits tyrosine phosphorylation of cellular proteins and Bcr-Abl in CML cells. Cancer Res. 2003 Jan 15;63(2):375-81.

    Bosutinib (SKI-606)

    SKI-606 is an Abl kinase inhibitor. Cancer Res. 2003 Jan 15;63(2):375-81.

    Bosutinib (SKI-606)

    Comparison of inhibition of Bcr-Abl tyrosine phosphorylation and v-Abl phosphorylation by SKI-606. Cancer Res.2003 Jan 15;63(2):375-81.

    Bosutinib (SKI-606)

    SKI-606 inhibits downstream signaling from Bcr-Abl. Cancer Res. 2003 Jan 15;63(2):375-81.

    Bosutinib (SKI-606)

    SKI-606 reduces phosphorylation of Tyr397 in Lyn.  Cancer Res. 2003 Jan 15;63(2):375-81.


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