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    ENMD-2076
    ENMD-2076

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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 #: V0363
    CAS #: 934353-76-1 (free base)Purity ≥98%

    Description: ENMD-2076 (ENMD2076) is a novel,potent and orally bioactive inhibitor of multikinase including Aurora A and Flt3 with potential antitumor activity. It inhibits Aurora A and Flt3 with IC50s of 14 nM and 1.86 nM, respectively, and exhibits 25-fold selectivity for Aurora A over Aurora B. It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy.

    References: Mol Cancer Ther. 2011 Jan;10(1):126-37;17(24):7614-24; Br J Haematol. 2010 Aug;150(3):313-25.

    Related CAS #: 1291074-87-7 (tartrate); 1453868-32-0 (tartrate); 934353-76-1 (free base);     

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    Molecular Weight (MW)375.47
    FormulaC21H25N7
    CAS No.934353-76-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 105 mg/mL (279.6 mM)
    Water: 1 mg/mL (2.7 mM)
    Ethanol: <1 mg/mL
    Solubility (In vivo)0.5% CMC+0.25% Tween 80: 30 mg/mL
    Synonyms

    Synonym: ENMD 2076; ENMD-2076; ENMD2076.

    Chemical Name: (E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine.

    InChi Key: BLQYVHBZHAISJM-CMDGGOBGSA-N

    InChi Code: InChI=1S/C21H25N7/c1-16-14-20(26-25-16)23-19-15-21(28-12-10-27(2)11-13-28)24-18(22-19)9-8-17-6-4-3-5-7-17/h3-9,14-15H,10-13H2,1-2H3,(H2,22,23,24,25,26)/b9-8+

    SMILES Code: CN1CCN(C2=CC(NC3=NNC(C)=C3)=NC(/C=C/C4=CC=CC=C4)=N2)CC1


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    In Vitro

    In vitro activity: ENMD-2076 indicates activity against multiple kinases involved in angiogenesis, including FLT3, RET, FLT4/VEGFR3, SRC, NTRK1, CSF1R/FMS, LCK, VEGFR2/KDR, FGFR1/2, and PDGFRα with IC50 from 1.86-120 nM. ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which induces apoptosis and G2/M phase arrest. ENMD-2076 induces regression or complete inhibition of tumor growth in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. ENMD-2076 is the L (+) tartrate salt of ENMD-981693. ENMD-2076 shows significant cytotoxicity against myeloma cell lines (IM9, ARH-77, U266, RPMI 8226, MM.1S, MM.1R, NCI-H929) and primary cells with IC50 from 2.99 to 7.06 μM, which induces apoptosis. ENMD-2076 indicates low cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates survivin and X-linked inhibitor of apoptosis. ENMD-2076 also inhibits aurora A and B kinases, and induces G2/M cell cycle arrest.


    Kinase Assay: Recombinant Aurora A and B kinase enzymes and appropriate PanVera Z'-Lyte kinase assay kits are purchased. Assays are carried out in kinase assay buffer (50 mM of HEPES, pH 7.5, 10 mM of MgCl2, 5 mM of EGTA, 0.05% Brij-35) supplemented with 2 mM of DTT. Activities are determined at an ATP concentration equivalent to the apparent Km for each enzyme, and an enzyme concentration that results in approximately 30% phosphorylation of the peptide substrate after 1 hour. Dose–response curves of relative enzyme activity versus ENMD-2076 concentration are plotted with Grafit and used to calculate IC50 values. Potency of ENMD-2076 free base against a select panel of 100 kinase enzymes is determined using the SelectScreen kinase profiling service. ATP concentrations are at the apparent Km for each enzyme or 100 μM if the apparent Km could not be reached. Percent inhibition is determined at an ENMD-2076 free base concentration of 1 μM; for kinases where significant inhibition is noted, IC50 values are determined by generating full 10-point dose–response curves.


    Cell Assay: The antiproliferative effect of ENMD-2076 on adherent tumor cell lines is measured by plating 500 cells (Human leukemia cell lines including MV4;11, U937, Kasumi, MO7e, HL-60, TF-1, Jurkat, K562, THP-1, Hel 92.1.7; Solid tumor cell lines and HUVEC including PANC-1, HCT116, A549, HT-29, MCF7, PC-3, BXPC-3 and HUVEC) per well in a 96-well plate and incubating with ENMD-2076 for 96 hours. Cellular proliferation is measured using the sulforhodamine B assay. The leukemia-derived, nonadherent cell lines are assayed by plating 5 × 103 cells per well in a 96-well plate. The cells are incubated with ENMD-2076 for 48 hours and then survival is assayed using the Alamar Blue reagent. To measure the effect of ENMD-2076 on VEGF- and fibroblast growth factor (FGF)-induced proliferation of human umbilical vein endothelial cell (HUVEC), cells are serum starved for 6 hours, then treated with ENMD-2076 free base, and stimulated with 5 ng/mL bFGF or 25 ng/mL VEGF (R and D Systems) for 72 hours. Cell proliferation is measured using WST.

    In VivoENMD-2076 has sustained inhibitory effects on the activation of Flt3 as well as VEGFR2/KDR and FGFR1/2 in HT29 xenograft model. ENMD-2076 could prevent the formation of new blood vessels and regress formed vessels in MDA-MB-231 xenograft model. Oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) inhibits the tumour growth in H929 human plasmacytoma xenografts, with significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3.
    Animal modelTumor models including HCT-116, HT29, CT-26, A375, MDA-MB-231, H929, OPM-2, MV4;11 and HL60 are established in CB.17 SCID or NCr nude mice.
    Formulation & DosageDissolved in water or ENMD-2076 free base in CMC-Tween vehicle (0.075% carboxymethylcellulose, 0.085% Tween 80 in water); 300 mg/kg;  Oral gavage
    References

    Mol Cancer Ther. 2011 Jan;10(1):126-37;17(24):7614-24; Br J Haematol. 2010 Aug;150(3):313-25.


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

    ENMD-2076

    Antiangiogenic action of ENMD-2076. Mol Cancer Ther. 2011 Jan;10(1):126-37.

    ENMD-2076

    ENMD-2076 inhibits Flt3, VEGFR2/KDR, FGFR-1/2, and Aurora A in vivo. Mol Cancer Ther. 2011 Jan;10(1):126-37.

    ENMD-2076

    ENMD-2076 inhibits blood vessel formation and impacts the growth of established MDA-MB-231 tumors. Mol Cancer Ther. 2011 Jan;10(1):126-37.


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