Pinometostat (EPZ5676)

Catalog No.S7062

Pinometostat (EPZ5676) Chemical Structure

Molecular Weight(MW): 562.71

Pinometostat (EPZ5676) is an S-adenosyl methionine (SAM) competitive inhibitor of protein methyltransferase DOT1L with Ki of 80 pM in a cell-free assay, demonstrating >37,000-fold selectivity against all other PMTs tested, inhibits H3K79 methylation in tumor. Phase 1.

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Cited by 19 Publications

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Biological Activity

Description Pinometostat (EPZ5676) is an S-adenosyl methionine (SAM) competitive inhibitor of protein methyltransferase DOT1L with Ki of 80 pM in a cell-free assay, demonstrating >37,000-fold selectivity against all other PMTs tested, inhibits H3K79 methylation in tumor. Phase 1.
Targets
DOT1L [1]
(Cell-free assay)
80 pM(Ki)
In vitro

EPZ-5676 reduces H3K79 dimethylation with a cellular IC50 of 2.6 nM in MV4-11 cells. EPZ-5676 treatment results in concentration- and time-dependent reduction of H3K79 methylation without effect on the methylation status of other histone sites, which leads to inhibition of key MLL target genes and selective, apoptotic cell killing in MLL-rearranged leukemia cells. EPZ-5676 inhibits proliferation of MLL-AF4 rearranged cell line MV4-11 with an IC50 of 9 nM.

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MV4-11 cells MlnuSpVv[3Srb36gZZN{[Xl? NUHicZBIPCCmYYnz NEjJWolKdmirYnn0bY9vKG:oIFTPWFFNKGmwIHj1cYFvKE2YND2xNUBk\WyuczDlfJBz\XO|aX7nJG1NVC2DRkSgZZN{\XO|ZXSgZZMhemWmdXP0bY9vKG:oIFizT|c6dWV{IHzleoVtKGGodHXyJFQh\GG7czDifUBGVEmVQTDt[ZRpd2R? MVuyOVQxPjh3Mx?=
human MOLM13 cells M{\je3Bzd2yrZnXyZZRqd25iYYPzZZk> NGrtTG5CdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIF3PUG0yOyClZXzsd{Bkd262YXnubY5oKE2OTD3BSlktKEWFNUC9OEBvVQ>? NUC1TYlWOjN6N{m0OlM>
human MV4-11 cells M3fXdXBzd2yrZnXyZZRqd25iYYPzZZk> MYDBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKE2YND2xNUBk\WyuczDjc451[WmwaX7nJG1NVC2DRkSsJGVEPTB;NDDuUS=> MUWyN|g4QTR4Mx?=
human THP1 cells NUDlXlR[WHKxbHnm[ZJifGmxbjDhd5NigQ>? NXPN[WNKSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDUTHAyKGOnbHzzJINwdnSjaX7pcochVUyOLVHGPUwhTUN3ME20JI5O NEG4Wm8zOzh5OUS2Ny=>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-p65 / p65 / NFATc1; 

PubMed: 29348610     


Murine RAW264.7 cells treated with DOT1L inhibitor or DMSO were stimulated with 10 ng/mL RANKL for the indicated time. The 40-h pre-OCs (40-h PreOC), 60-h pre-OCs (60-h PreOC), and 60-h OCs (60-h OC) were collected for western blot analysis. Phosphorylation of p65 on S536 and NFATc1 expression were detected with specific antibodies; grayscale analysis was conducted using p65 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the internal controls, respectively.

CDK6 / BCL11A / Bcl-2 / RUNX1 / MEF2C / H3K79me3 / H4; 

PubMed: 28076791     


Western blot showing the protein expression of several spreading MLL-AF4 targets and controls in the presence of control, 0.5, 1, or 2 μM EPZ-5676 treatments. Blue and red boxes relate to treatment colors in (A) that led to the lowest level of treatment that resulted in reduced gene transcription.

29348610 28076791
Immunofluorescence
NFATc1; 

PubMed: 29348610     


Immunofluorescence analysis of NFATc1 nuclear translocation. RAW264.7 cells were treated with DMSO or 1 µM EPZ5676 for 40 h. Red color indicates NFATc1 expression, as seen under a fluorescence microscope, and the nuclei are stained blue. Representative results of the two replica experiments are shown (magnification, ×600). 

29348610
In vivo EPZ-5676 continuously intravenous infusion for 21 days to xenograft model of MLL-rearranged leukemia, leads to dose-dependent anti-tumor activity. At the highest dose of 70.5 mg/kg/day, complete tumor regressions are achieved with no regrowth for up to 32 days after the cessation of treatment. No significant weight loss or obvious toxicity is observed in rats treated with EPZ-5676 during efficacy study.

Protocol

Solubility (25°C)

In vitro DMSO 100 mg/mL warmed (177.71 mM)
Ethanol 92 mg/mL warmed (163.49 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.
5mg/mL

* 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 562.71
Formula

C30H42N8O3

CAS No. 1380288-87-8
Storage powder
in solvent
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

Tel: +1-832-582-8158 Ext:3

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Frequently Asked Questions

  • Question 1:

    Is the vehicle 30% PEG400/0.5% Tween80/5% propylene glycol recommended for in vivo use?

  • Answer:

    S7062 EPZ-5676 in 30% PEG400/0.5% Tween80/5% propylene glycol at 30 mg/ml is a suspension. For injection, 2% DMSO/30% PEG 300/5% Tween 80/ddH2O at 5 mg/ml is suitable.

Histone Methyltransferase Signaling Pathway Map

Histone Methyltransferase Inhibitors with Unique Features

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID