EPZ005687

Catalog No.S7004

EPZ005687 is a potent and selective inhibitor of EZH2 with Ki of 24 nM in a cell-free assay, 50-fold selectivity against EZH1 and 500-fold selectivity against 15 other protein methyltransferases.

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EPZ005687 Chemical Structure

EPZ005687 Chemical Structure
Molecular Weight: 539.67

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Product Information

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Product Description

Biological Activity

Description EPZ005687 is a potent and selective inhibitor of EZH2 with Ki of 24 nM in a cell-free assay, 50-fold selectivity against EZH1 and 500-fold selectivity against 15 other protein methyltransferases.
Targets EZH2 [1]
(Cell-free assay)
IC50 24 nM(Ki)
In vitro EPZ005687 shows concentration-dependent inhibition of PRC2 enzymatic activity with an IC50 value of 54 nM. It is a direct inhibitor of PRC2 enzymatic activity and does not function by disrupting the protein-protein interactions among the PRC2 subunits. EPZ005687 binds in the SAM pocket of the EZH2 SET domain and is a SAM-competitive inhibitor of EZH2 enzyme activity. The affinity of EPZ005687 is similar (within a two-fold range) for PRC2 complexes containing wild-type and Tyr641 mutant EZH2, but significantly greater affinity for the A677G mutant enzyme (5.4-fold). EPZ005687 reduces H3K27 methylation in various lymphoma cells. It shows robust cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. EPZ005687 increases G1 phase of the cell cycle with correlative decreases in the S as well as the G2/M phases. In a Tyr641 mutant lymphoma cell line, EPZ005687 can lead to derepression of known EZH2 target genes and affect genes specifically repressed by the EZH2 Tyr641 mutant. [1]
In vivo
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Biochemical Enzyme Assays Compound is incubated for 30 min with 40 μL per well of 5 nM PRC2 (final assay concentration in 50 μL is 4 nM ) in 1X assay buffer (20 mM Bicine [pH 7.6], 0.002% Tween-20, 0.005% Bovine Skin Gelatin and 0.5 mM DTT). 10 μL per well of substrate mix comprising assay buffer 3 H-SAM, unlabeled SAM, and peptide representing histone H3 residues 21-44 containing C-terminal biotin (appended to a C-terminal amide-capped lysine) are added to initiate the reaction (both substrates are present in the final reaction mixture at their respective Km values, an assay format referred to as ‘‘balanced conditions’’. The final concentrations of substrates and methylation state of the substrate peptide are indicated for each enzyme Reactions are incubated for 90 min at room temperature and quenched with 10 μL per well of 600 μM unlabeled SAM, Then transferred to a 384-well flashplate and washed after 30 min.

Cell Assay: [1]

Cell lines OCI-LY19, WSU-DLCL2, Pfeiffer
Concentrations ~10 μM
Incubation Time 11 days
Method Plating densities are determined for each cell line on the basis of linear log-phase growth. Cells are counted and split back to the original plating density in fresh medium with EPZ005687 on days 4 and 7.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Knutson SK, et al. Nat Chem Biol, 2012, 8(11), 890-896.

Chemical Information

Download EPZ005687 SDF
Molecular Weight (MW) 539.67
Formula

C32H37N5O3

CAS No. 1396772-26-1
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 2 mg/mL (3.7 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
* <1 mg/ml means slightly soluble or 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 Name 1H-Indazole-4-carboxamide, 1-cyclopentyl-N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-6-[4-(4-morpholinylmethyl)phenyl]-

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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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