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    EPZ004777
    EPZ004777

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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 #: V0401
    CAS #: 1338466-77-5 (free)Purity ≥98%

    Description: EPZ004777 (EPZ-004777) is a potent and selective inhibitor of  DOT1 Like Histone Lysine Methyltransferase (DOT1L) inhibitor with antineoplastic activity. It inhibits DOT1L with an IC50 of 0.4 nM in a cell-free assay. It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. Exposure of leukemic cells to EPZ 004777 laed to selective killing of cells bearing MLL gene translocation, with little effect on non-MLL-translocated cells. In addition, EPZ004777 extended the survival of mice bearing a MLL xenograft model.

    References: Leukemia. 2013 Apr;27(4):813-22; Cancer Cell. 2011 Jul 12;20(1):53-65.

    Related CAS: 1380316-03-9 (HCl)

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    Molecular Weight (MW)539.67
    FormulaC28H41N7O4
    CAS No.1338466-77-5
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (185.3 mM)
    Water:<1 mg/mL 
    Ethanol: 100 mg/mL (185.3 mM)
    Other infoChemical Name: 1-(3-((((2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea
    InChi Key: WXRGFPHDRFQODR-ICLZECGLSA-N
    InChi Code: InChI=1S/C28H41N7O4/c1-17(2)34(13-6-12-30-27(38)33-19-9-7-18(8-10-19)28(3,4)5)15-21-22(36)23(37)26(39-21)35-14-11-20-24(29)31-16-32-25(20)35/h7-11,14,16-17,21-23,26,36-37H,6,12-13,15H2,1-5H3,(H2,29,31,32)(H2,30,33,38)/t21-,22-,23-,26-/m1/s1
    SMILES Code: O=C(NC1=CC=C(C(C)(C)C)C=C1)NCCCN(C[[email protected]]2O[[email protected]@H](N3C=CC4=C(N)N=CN=C43)[[email protected]](O)[[email protected]@H]2O)C(C)C
    SynonymsEPZ 004777; EPZ-004777; EPZ004777


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    In Vitro

    In vitro activity: EPZ004777 selectively inhibits cellular H3K79 methylation and inhibits expression of key MLL fusion target genes. Following DOT1L inhibition, EPZ004777 selectively inhibits proliferation of MLL-Rearranged cell lines and MLL-AF9-transformed murine hematopoietic cells. In addition, EPZ004777 also induces differentiation and apoptosis in MLL-rearranged cells. EPZ004777 selectively inhibits proliferation of MLL–AF10 and CALM–AF10-transformed murine bone marrow cells. DOT1L inhibition by EPZ004777 results in significantly decreased proliferation, decreased expression of MLL-AF6 target genes, and cell cycle arrest of MLL-AF6-transformed cells.


    Kinase Assay: EPZ004777 is serially diluted 3-fold in DMSO for a total of ten concentrations, beginning at 1 mM. A 1 μL aliquot of each inhibitor dilution is plated in a 384-well microtiter plate. The 100% inhibition control consisted of 2.5 mM final concentration of the product inhibitor S-adenosyl-L-homocysteine, (SAH). Compound is incubated for 30 min with 40 ml per well of 0.25 nM DOT1L(1-416) in assay buffer (20 mM TRIS [pH 8.0] 10 mM NaCl, 0.002% Tween 20, 0.005% Bovine Skin Gelatin, 100 mM KCl, and 0.5 mM DTT). 10 ml per well of substrate mix comprising assay buffer with 200 nM 3H-SAM (American Radiolabeled Chemicals: 80 Ci/mmol), 600 nM unlabeled SAM, and 20 nM nucleosomes are added to initiate the reaction (both substrates are present in the final reaction mixture at their respective KM values). Reactions are incubated for 120 min and quenched with 10 ml per well of 800 mM SAM. Incorporation of radioactivity into nucleosome substrate is measured in a flashplate. IC50 values for enzymes in the histone methyltransferase panel are determined under similar balanced assay conditions with both SAM and protein/peptide substrate present at concentrations equal to their respective KM values.


    Cell Assay: For assessment of cell proliferation and viability in human cell lines, exponentially growing cells are plated, in triplicate, in 96-well plates in a final volume of 150 ml. Cells are incubated in the presence of 3 μM (proliferation curve), or increasing concentrations (IC50 determination) of EPZ004777 up to 50 μM. Viable cell number is determined every 3–4 days for up to 18 days using the Guava Viacount assay and analyzed on a Guava EasyCyte Plus instrument according to the manufacturer’s protocol. On days of cell counts, growth media and EPZ004777 are replaced and cells split back to a density of 5×104 cells/well. Total cell number is expressed as split-adjusted viable cells per well. For each cell line, IC50 values are determined from concentration-dependence curves at each time point using Graphpad Prism software. Experiments to determine IC50 values continues until IC50 values stabilized (day 18 for THP-1 cells, day 14 for all other cell lines). For assessment of the effect of EPZ004777 treatment on transformed murine hematopoietic progenitors, cells from two independent transductions for each virus are plated in 24-well plates at a density of 0.5–1×105 cell/well in 1 ml media in 24-well plates and exposed to increasing concentrations of EPZ004777 up to 30 mM. Cells are counted and replated at equal cell numbers in fresh media with fresh compound every 3–4 days. For MTT assays, cells from serial replatings are harvested on day 10 and plated, in triplicate at 2×104 cells/well in 100 ml media with the appropriate concentration of EPZ004777. Cells are incubated for 2.5 days, the exposed to 10 ml MTT reagent for 3 hr, and lysed over night in 100 ml MTT- solubilization buffer (both from Cell Proliferation Kit I [MTT]).

    In VivoEPZ004777 produces potent antitumor efficacy, and significantly increases median survival in a mouse xenograft model of MLL leukemia
    Animal modelA mouse xenograft MV4-11 model of MLL.
    Formulation & DosageDissolved in 15% ethanol, 50% PEG300, 35% water; Mini-pumps containing 100 and 150 mg/mL EPZ004777 solutions; Osmotic pump
    References

    Leukemia. 2013 Apr;27(4):813-22; Cancer Cell. 2011 Jul 12;20(1):53-65.


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

    EPZ004777
    In Vivo Activity of EPZ004777. Cancer Cell. 2011 Jul 12; 20(1): 53–65.



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