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    AC480 (BMS599626)
    AC480 (BMS599626)

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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 #: V0554
    CAS #: 714971-09-2Purity ≥98%

    Description: AC480 (also known as BMS-599626) is a novel, potent, orally bioavailable, selective and efficacious inhibitor of HER1/2 (human epidermal growth factor receptors) with potential anticancer activity. It inhibits HER1/2 with IC50s of 20 nM and 30 nM, respectively. It shows ~8-fold less potency against HER4, and is >100-fold less active to VEGFR2, c-Kit, Lck, MET etc. Oral administration of AC480 has been demonstrated to suppress the growth of Sal2 tumor, GEO xenograft tumor, KPL-4 and BT474 breast tumors, N87 gastric tumor, A549 and L2987 non–small-cell lung tumors in nude mice.

    References: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93; Invest New Drugs. 2011 Aug;29(4):554-61.

    Related CAS: 714971-09-2 (free base); 873837-23-1 (HCl salt)

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    Molecular Weight (MW)530.55
    FormulaC27H27FN8O3
    CAS No.714971-09-2 (free base)
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 113 mg/mL (213.0 mM)
    Water: <1 mg/mL
    Ethanol: 20 mg/mL (37.7 mM)
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL 
    SynonymsBMS-599626; BMS599626; BMS 599626; AC 480; AC-480; AC 480 hydrochloride; BMS599626 HCl; BMS599626 hydrochloride; AC480; AC 480 HCl; 


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    In Vitro

    In vitro activity: BMS-599626 also inhibits the related receptor HER4, but with reduced potency with IC50 of 190 nM. BMS-599626 is identified as an ATP-competitive inhibitor for HER1 and as an ATP-noncompetitive inhibitor for HER2 with Ki of 2 nM and 5 nM, respectively. BMS-599626 inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2, including Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, and PC9 cells with IC50 of 0.24 μM, 0.31 μM, 0.45 μM, 0.38μM, 0.94 μM, 0.34 μM, 0.75 μM, 0.63 μM, 0.51 μM, 0.84 μM, 0.90 μM and 0.34 μM, respectively. While the proliferation of the ovarian tumor cell line A2780 and MRC5 fibroblasts, neither of which expresses HER1 or HER2, are not inhibited significant by BMS-599626. A recent study shows that BMS-599626 significantly enhances the radiosensitivity of HN-5 cells expressing both EGFR and Her2 cell, by promoting cycle redistribution and inhibiting DNA repair.


    Kinase Assay: The entire cytoplasmic sequences of HER1, HER2, and HER4 are expressed as recombinant proteins in Sf9 insect cells. HER1 and HER4 are expressed as fusion proteins with glutathione-S-transferase and are purified by affinity chromatography on glutathione-S-Sepharose. HER2 is subcloned into the pBlueBac4 vector and expressed as an untagged protein using an internal methionine codon (M687) for translation initiation. The truncated HER2 protein is isolated by chromatography on a column of DEAE-Sepharose equilibrated in a buffer that contains 0.1 M NaCl, and the recombinant protein is eluted with a buffer containing 0.3 M NaCl. For the HER kinase assays, reaction volumes are 50 μL and contains 10 ng of glutathione-S-transferase fusion protein or 150 ng of partially purified HER2. The mixtures also contains 1.5 μM poly(Glu/Tyr) (4:1), 1 μM ATP, 0.15 μCi [γ-33P]ATP, 50 mM Tris-HCl (pH 7.7), 2 mM DTT, 0.1 mg/mL bovine serum albumin, and 10 mM MnCl2. Reactions are allowed to proceed at 27°C for 1 hour and are terminated by the addition of 10 μL of a stop buffer (2.5 mg/mL bovine serum albumin and 0.3 M EDTA), followed by a 108-μL mixture of 3.5 mM ATP and 5% trichloroacetic acid. Acid-insoluble proteins are recovered on GF/C Unifilter plates with a Filtermate harvester. Incorporation of radioactive phosphate into the poly(Glu/Tyr) substrate is determined by liquid scintillation counting. Percent inhibition of kinase activity is determined by nonlinear regression analyses and data are reported as the inhibitory concentration required to achieve 50% inhibition relative to control reactions (IC50). Data are the averages of triplicate determinations. All other tyrosine kinases are also assayed using poly(Glu/Tyr) as a substrate. Kinetics of HER1 and HER2 inhibition are determined in reaction mixtures that contains varying concentrations of ATP and BMS-599626.


    Cell Assay: All cell lines are maintained in RPMI 1640 supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 μg/mL streptomycin. Cells are plated at 1,000 per well in 96-well plates and are cultured for 24 hours before BMS-599626 is added. BMS-599626 is diluted in culture medium such that the final concentrations of DMSO are ≤ 1%. Following the addition of BMS-599626, the cells are cultured for an additional 72 hours before cell viability is determined by measuring the conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye with the CellTiter96 kit. For some cell lines, there is a lack of a correlation between 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye metabolism and cell number, and a thymidine uptake assay is used to measure proliferation of these cell lines. Cells are plated in 96-well plates and treated with compounds as above. At the end of the 72-hour incubation, cells are pulsed with [3H]thymidine (0.4 μCi/well) for 3 hours before they are harvested. Cells are digested with 2.5% trypsin for 10 minutes at 37 °C and are harvested by filtration using a Packard Filtermate Harvester and GF/C Unifilter plates. Incorporation of radioactive thymidine into nucleic acids is determined by liquid scintillation counting.

    In VivoIn vivo, oral administration of BMS-599626 results in a dose-dependent inhibition of Sal2 tumor growth at doses ranging from 60 mg/kg to 240 mg/kg, yielding a potent antitumor activity in a human breast tumor KPL-4 xenograft at its maximum tolerated dose of 180 mg/kg, and also has similar antitumor activity in other HER2 amplified xenograft models, as well as other HER1-overexpressing xenograft models.
    Animal modelSAL2 murine salivary gland tumor, N87 human gastric carcinoma, BT474 human breast tumor, A549 human non–small-cell lung tumor, and GEO human colon tumor are maintained and passaged in athymic female nude mice.
    Formulation & DosageDissolved in a mixture of propylene glycol/water (50:50);  ≤240 mg/kg; Oral gavage
    References

    Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93; Invest New Drugs. 2011 Aug;29(4):554-61.


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

    AC480 (BMS-599626)

    BMS-599626 inhibits HER1/HER2 heterodimer formation. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93.

    AC480 (BMS-599626)

    Antitumor activity of BMS-599626. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93.

    AC480 (BMS-599626)

    Pharmacokinetics of BMS-599626 and pharmacodynamic assessment of Sal2 tumor inhibition by BMS-599626. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93.


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