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    AEE788 (NVP-AEE788)
    AEE788 (NVP-AEE788)

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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 #: V0504
    CAS #: 497839-62-0Purity ≥98%

    Description: AEE788 (NVP-AEE-788; NVP-AEE788) is a novel, potent and orally bioavailable inhibitor of multiple receptor tyrosine kinase such as EGFR (epidermal growth factor receptor) and HER2/ErbB2 with potential antitumor activity. It inhibits EGFR and HER2/ErbB2 with IC50s of 2 nM and 6 nM, and is less potent against VEGFR2/KDR, c-Abl, c-Src, and Flt-1. No effects on Ins-R, IGF-1R, PKCα and CDK1. AEE788 inhibits phosphorylation of the tyrosine kinases of EGFR, HER2, and VEGF2, resulting in inhibition of cellular proliferation, and induction of tumor cell and tumor-associated endothelial cell apoptosis.

    References: Cancer Res. 2004;64(14):4931-41; Cancer Res. 2005;65(9):3716-25; Clin Cancer Res. 2007;13(4):1140-8.

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    Molecular Weight (MW)440.58
    FormulaC27H32N6
    CAS No.497839-62-0
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 88 mg/mL (199.7 mM)
    Water: <1 mg/mL
    Ethanol:<1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
    SynonymsNVP-AEE788; NVP-AEE-788; NVP-AEE 788; AEE 788; AEE-788; AEE788;  

    Chemical Name: (R)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

    InChi Key: OONFNUWBHFSNBT-HXUWFJFHSA-N

    InChi Code: InChI=1S/C27H32N6/c1-3-32-13-15-33(16-14-32)18-21-9-11-23(12-10-21)25-17-24-26(28-19-29-27(24)31-25)30-20(2)22-7-5-4-6-8-22/h4-12,17,19-20H,3,13-16,18H2,1-2H3,(H2,28,29,30,31)/t20-/m1/s1

    SMILES Code: C[[email protected]@H](NC1=C2C(NC(C3=CC=C(CN4CCN(CC)CC4)C=C3)=C2)=NC=N1)C5=CC=CC=C5


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    In Vitro

    In vitro activity: AEE788 also inhibits KDR, c-abl, c-Src, and Flt-1 with IC50 of 50-80 nM. AEE788 is not sensitive to ErbB-4, PDGFR-β, Flt-3, Flt-4, RET, and c-Kit and has no inhibitory to Ins-R, IGF-1R, PKC-α, and PKA. AEE788 potently inhibits EGFR phosphorylation in A431 cells with IC50 of 11 nM. AEE788 also inhibits the phosphorylation of KDR in CHO cells and erbB2 in BT-474 cells, without any effects on PDGF-induced phosphorylation in A31 cells. AEE788 inhibits the proliferation of NCI-H596, MK, BT-474 and SK-BR-3 cells with IC50 of 78, 56, 49 and 381 nM, respectively. Otherwise, AEE788 has the additional property of inhibiting cellular proliferation driven by EGFR mutant including 32D/EGFR and 32D/EGFRvIII. AEE788 furtheralso inhibits both EGF- and VEGF-driven HUVEC proliferation with IC50 of 43 and 155 nM, respectively. AEE788 inhibits the phosphorylation of EGFR, VEGFR2, Akt, and MAPK in human cutaneous SCC cell lines (Colo16, HaCaT, SRB1, and SRB12 cells), which leads to growth inhibition and induction of apoptosis. AEE788 inhibits the phosphorylation of EGFR and Akt in HT29 cells at 0.2 to 1.0 μM. AEE788 inhibits cell proliferation and prevents EGF- and neuregulin-induced HER1, HER2, and HER3 activation in medulloblastoma cell lines. AEE788 shows growth-suppressive activities in chemosensitive and chemoresistant medulloblastoma cells.


    Kinase Assay: The in vitro kinase assays are performed in 96-well plates (30 μL) at ambient temperature for 15–45 min using the recombinant glutathione S-transferase-fused kinase domains (4-100 ng, depending on specific activity). [γ33P]ATP is used as phosphate donor and polyGluTyr-(4:1) peptide as acceptor. With the exception of protein kinase C-α, cyclin-dependent kinase 1/cycB and protein kinase A are protamine sulfate (200 μg/mL), histone H1 (100 μg/mL), and the heptapeptide Leu-Arg-Arg-Ala-Ser-Leu-Gly (known as Kemptide Bachem) respectively and are used as peptide substrates. Assays are optimized for each kinase using the following ATP concentrations: 1.0 μM (c-Kit, c-Met, c-Fms, c-Raf-1, and RET), 2.0 μM (EGFR, erbB2, ErbB3, and ErbB4), 5.0 μM (c-abl), 8.0 μM (Flt-1, Flt-3, Flt-4, Flk, KDR, FGFR-1, and Tek), 10.0 μM (PDGFR-β, protein kinase C-α, and cyclin-dependent kinase 1), and 20.0 μM (c-Src and protein kinase A). The reaction is terminated by the addition of 20 μL 125 mM EDTA. Thirty μL (c-abl, c-Src, insulin-like growth factor-1R, RET-Men2A, and RET-Men2B) or 40 μL (all other kinases) of the reaction mixture is transferred onto Immobilon-polyvinylidene difluoride membrane, presoaked with 0.5% H3PO4 and mounted on a vacuum manifold. Vacuum is then applied and each well rinsed with 200 μL 0.5% H3PO4. Membranes are removed and washed four times with 1.0% H3PO4 and once with ethanol. Dried membranes are counted after mounting in a Packard TopCount 96-well frame and with the addition of 10 μL/well of Microscint. IC50 values (±SE) are calculated by linear regression analysis of the percentage inhibition and are averages of at least three determinations. 


    Cell Assay: Methylene Blue Cell Proliferation Assay.Cells are seeded at 1.5 × 103 cells/well into 96-well microtiter plates and incubated overnight at 37 °C, 5% v/v CO2 and 80% relative humidity. AEE788 dilutions are added on day 1, with the highest concentration being 10 μM. After incubation of the cell plates for an additional 4 (T24) or 6 (BT-474, SK-BR-3, and NCI-H596) days, cells are fixed with 3.3% v/v glutaraldehyde, washed with water, and stained with 0.05% w/v methylene blue. After washing, the dye is eluted with 3% HCl and the absorbance measured at 665 nm with a SpectraMax 340 spectrophotometer. IC50 values are determined by mathematical curve-fitting and are defined as the drug concentration leading to 50% inhibition of net cell mass increase compared with untreated control cultures.

    In VivoAEE788 produces a dose-dependent inhibition of tumor growth in NCI-H596 or DU145 xenograft models, with only minor body weight changes. AEE788 induces tumor regression by 57% at 50 mg/kg in the NeuT/erbB2 GeMag model. AEE788 potently inhibits EGF-induced EGFR phosphorylation in A431 tumors and erbB2 phosphorylation in GeMag tumors. AEE788 dose-dependently inhibited angiogenesis induced by VEGF and does not inhibit bFGF-induced angiogenesis. AEE788 suppresses the growth of tumor volume by 54% in Colo16 xenografts at 50 mg/kg, which dues to the inhibition of phosphorylation of EGFR, VEGFR, Akt, and MAPK. AEE788 (50 mg/kg) also inhibits growth of tumors in the cecum and peritoneum (>50%) and reduces the incidence of lymph node metastasis to 70% in HT29 cells implanted in the cecum of nude mice, without loss of body weight and gross evidence of neovascularization. AEE788 significantly lowers the expression levels of pEGFR and pVEGFR in HT29 cecal tumors and does not alter those of EGF, VEGF, EGFR, or VEGFR. Combined with CPT-11, AEE788 has significantly smaller tumors and complete inhibition of lymph node metastasis. AEE788 inhibits the growth of Daoy, DaoyPt, and DaoyHER2 xenografts by 51%, 45%, and 72%, respectively. AEE788 could promote LBH589-mediated generation of reactive oxygen species in K562 tumor cells, which in turn increase apoptosis.
    Animal modelNCI-H596, DU145, A431, B16 and oncogenic NeuT-transfected HC11 cells in female BALB/c nu/nu (nude) mice
    Formulation & DosageFormulated in N-methylpyrrolidone and PEG300 1:9 (v/v); 50mg/kg; oral gavage
    References

    Cancer Res. 2004 Jul 15;64(14):4931-41; Cancer Res. 2005 May 1;65(9):3716-25; Clin Cancer Res. 2007 Feb 15;13(4):1140-8.


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

    AEE788 (NVP-AEE788)

    Immunohistochemical analysis of human colon cancer surgical specimens for expression of TGF-α, EGF, EGFR, pEGFR, VEGF, VEGFR, pVEGFR, and CD31. Cancer Res. 2005 May 1;65(9):3716-25.

    AEE788 (NVP-AEE788)

    Double-immunofluorescence staining for expression of EGFR, pEGFR, VEGFR, or pVEGFR in tumor-associated endothelial cells. Cancer Res. 2005 May 1;65(9):3716-25.

    AEE788 (NVP-AEE788)

    Analysis for cell proliferation, apoptosis, and microvessel density. A, mice were treated with saline (control), AEE788, CPT-11, or the combination of AEE788 and CPT-11. Cecal tumors were excised and processed for immunohistochemical analysis. B, double-immunofluorescence staining of CD31/PECAM-1 and TUNEL (apoptosis) tumors from mice treated with the combination of AEE788 and CPT-11. Cancer Res. 2005 May 1;65(9):3716-25.


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