EPZ004777

Catalog No.S7353

EPZ004777 Chemical Structure

Molecular Weight(MW): 539.67

EPZ004777 is a potent, selective DOT1L inhibitor with IC50 of 0.4 nM in a cell-free assay and demonstrates >1,200-fold selectivity for DOT1L over all other tested PMTs.

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1 Customer Review

  • THP-1 cells were treated with MI-3 (6.25 μM, 6 days), GSK126 (5 μM, 6 days), or EPZ004777 (5 μM, 6 days), with orwithout PMA (50 ng/mL, 12 h), and surface expression of CD11b was determined by flow cytometric analysis. The data are representedas the mean ± SD, n = 3. THP-1 cells were collected for Wright-Giemsa staining.

    FEBS J, 2017. EPZ004777 purchased from Selleck.

Purity & Quality Control

Choose Selective Histone Methyltransferase Inhibitors

Biological Activity

Description EPZ004777 is a potent, selective DOT1L inhibitor with IC50 of 0.4 nM in a cell-free assay and demonstrates >1,200-fold selectivity for DOT1L over all other tested PMTs.
Targets
DOT1L [1]
(Cell-free assay)
0.4 nM
In vitro

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. [1] EPZ004777 selectively inhibits proliferation of MLL–AF10 and CALM–AF10-transformed murine bone marrow cells. [2] 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. [3]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MOLM13 cells NWXoUVZYWHKxbHnm[ZJifGmxbjDhd5NigQ>? MnPjRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCPT1zNNVMh[2WubIOgZ49vfGGrbnnu[{BOVExvQV[5MEBGSzVyPUSgcm0> MWiyN|g4QTR4Mx?=
human MV4-11 cells MYfQdo9tcW[ncnH0bY9vKGG|c3H5 NVfqSnkxSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDNWlQuOTFiY3XscJMh[2:wdHHpcolv\yCPTFytRWY1NCCHQ{WwQVQhdk1? NVvkRYg4OjN6N{m0OlM>
human THP1 cells NHfKOnlRem:uaX\ldoF1cW:wIHHzd4F6 MVfBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKFSKUEGgZ4VtdHNiY3;ueIFqdmmwZzDNUGwuSUZ7LDDJR|UxRTRibl2= MnXFNlM5Pzl2NkO=
human MCF10A cells M{C2ZWZ2dmO2aX;uJIF{e2G7 NFvIb3pKdmirYnn0bY9vKG:oIFTPWFFNKGmwIHj1cYFvKE2FRkGwRUBk\WyuczDhd5Nme3OnZDDhd{Bz\WS3Y4Tpc44hd2ZiSEPLO|khdGW4ZX|vwKwhUUN3ME24OEBvVQ>? NWD1eINuOjV2ME[4OVM>
human MLL cells NWf5UlEzTnWwY4Tpc44h[XO|YYm= Mo\2TY5pcWKrdHnvckBw\iCKb4jhPUBidmRiTXXpd|Eh\2WwZTDlfJBz\XO|aX;uJIlvKGi3bXHuJG1NVCClZXzsdy=> MWiyN|g4QTR4Mx?=
Sf9 cells MWPGeY5kfGmxbjDhd5NigQ>? NFvqWnpKdmirYnn0bY9vKG:oIHj1cYFvKG[3bHygcIVv\3SqIGDSUXQ4KGW6cILld5Nm\CCrbjDT[lkh[2WubIOsJGlEPTB;Nz61JO69VQ>? MlzqNlU5QTNyNEG=

... Click to View More Cell Line Experimental Data

In vivo EPZ004777 produces potent antitumor efficacy, and significantly increases median survival in a mouse xenograft model of MLL leukemia. [1]

Protocol

Kinase Assay:

[1]

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Determination of Inhibitor IC50 Values:

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 Research:

[1]

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  • Cell lines: Human leukemia cell lines MV4-11, THP-1, RS4;11, Kasumi-1, HL-60, REH, and Jurkat. SEM, KOPN-8, 697, U937 and MOLM-13 cells.
  • Concentrations: ~50 μM
  • Incubation Time: 14-18 days
  • Method:

    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]).


    (Only for Reference)
Animal Research:

[1]

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  • Animal Models: A mouse xenograft MV4-11 model of MLL.
  • Formulation: 15% ethanol, 50% PEG300, 35% water
  • Dosages: Mini-pumps containing 100 and 150 mg/mL EPZ004777 solutions
  • Administration: Osmotic pump
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (185.29 mM)
Ethanol 100 mg/mL (185.29 mM)
Water Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 539.67
Formula

C28H41N7O4

CAS No. 1338466-77-5
Storage powder
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Related Antibodies

Histone Methyltransferase Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID