Home Epigenetics Histone Methyltransferase inhibitor - EZH1/2 inhibitor Tazemetostat (EPZ-6438) For research use only.

Tazemetostat (EPZ-6438)

Synonyms: E7438

Tazemetostat (EPZ-6438, E7438) is a potent, and selective EZH2 inhibitor with Ki and IC50 of 2.5 nM and 11 nM in cell-free assays, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs.

Tazemetostat (EPZ-6438) Chemical Structure

Tazemetostat (EPZ-6438) Chemical Structure

CAS No. 1403254-99-8

Purity & Quality Control

Tazemetostat (EPZ-6438) Related Products

Signaling Pathway

Histone Methyltransferase Signaling Pathways

Histone Methyltransferase Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human HeLa cells Function assay 72 h Inhibition of EZH2 in human HeLa cells assessed as reduction in H3K27me3 levels incubated for 72 hrs by ELISA method, IC50=0.02 μM. 26189078
Sf9 Function assay 2 h Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fl, IC50 = 0.004 μM. 29456795
KARPAS422 Antiproliferative activity assay 3 to 4 days up to 14 days Antiproliferative activity against human KARPAS422 cells harboring monoallelic Y641N EZH2 mutation assessed as reduction in cell viability measured every 3 to 4 days up to 14 days by Beckman Coulter-based method, IC50 = 0.012 μM. 28092155
Pfeiffer Cytotoxicity assay 5 days Cytotoxicity against human Pfeiffer cells assessed as decrease in cell viability after 5 days by CellTiter-Glo reagent based luminescence assay, IC50 = 0.038 μM. 29456795
G401 Function assay 48 h Inhibition of EED in human G401 cells assessed as reduction in global H3K27me3 level after 48 hrs by ELISA, IC50 = 0.04 μM. 28092155
G401 Function assay 4 h Inhibition of methyltransferase activity of EZH2 in human G401 cells assessed as H3K27 trimethylation after 4 hrs by ELISA, EC50 = 0.2 μM. 26769278
Pfeiffer Antitumor assay 100 mg/kg 20 days Antitumor activity against human Pfeiffer cells xenografted in athymic nude mouse assessed as tumor growth inhibition at 100 mg/kg, po qd administered for 20 days measured twice per week 29456795
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Biological Activity

Description Tazemetostat (EPZ-6438, E7438) is a potent, and selective EZH2 inhibitor with Ki and IC50 of 2.5 nM and 11 nM in cell-free assays, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs.
Features Orally bioavailable EZH2-selective inhibitor for both wild-type and mutant. Currently being tested in Phase II clinical trials for treatment of Diffuse Large B Cell Lymphoma.
Targets
EZH2 [1]
(Cell-free assay)
2.5 nM(Ki)
In vitro
In vitro

EPZ-6438 concentration-dependently reduces global H3K27Me3 levels in wild-type or SMARCB1 mutant cells, and induces strong antiproliferative effects with IC50 ranging from 32 nM to 1000 nM in SMARCB1-deleted MRT cell lines. EPZ-6438 induces gene expression of neuronal differentiation and cell cycle inhibition, while inhibtis expression of Hedgehog pathway genes, MYC and EZH2. [1] The antiproliferative effect of EPZ-6438 is enhanced by either NSC-9900 or Hexadecadrol in several EZH2 mutant lymphoma cell lines. [2]
Kinase Assay Biochemical Methods
EPZ-6438 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 Research Cell lines Mutant cell lines (G401, A204, G402, KYM-1), Wild type cell line (RD, 293, SJCRH30)
Concentrations ~10 μM
Incubation Time 7 days
Method

For the adherent cell line proliferation assays, plating densities for each cell line are determined based on growth curves (measured by ATP content) and density over a 7-d time course. On the day before compound treatment, cells are plated in either 96-well plates in triplicate (for the day 0–7 time course) or 6-well plates (for replating on day 7 for the remainder of the time course). On day 0, cells are either untreated, DMSO-treated, or treated with EPZ-6438 starting at 10 µM and decreasing in either threefold or fourfold dilutions. Plates are read on day 0, day 4, and day 7 using Cell Titer Glo, with compound/media being replenished on day 4. On day 7, the six-well plates are trypsinized, centrifuged, and resuspended in fresh media for counting by Vi-Cell. Cells from each treatment are replated at the original density in 96-well plates in triplicate. Cells are allowed to adhere to the plate overnight, and cells are treated as on day 0. On days 7, 11, and 14, plates are read using Cell Titer Glo, with compound/media being replenished on day 11. Averages of triplicates are used to plot proliferation over the time course, and calculate IC50 values. For cell cycle and apoptosis, G401 and RD cells are plated in 15-cm dishes in duplicate at a density of 1 × 106 cells per plate. Cells are incubated with EPZ-6438 at 1 µM, in a total of 25 mL, over a course of 14 d, with cells being split back to original plating density on day 4, 7, and 11. Cell cycle analysis and TUNEL assay are performed using a Guava flow cytometer, following the manufacturer’s protocol.
Experimental Result Images Methods Biomarkers Images PMID
Western blot H3K27me3 EZH2 29670078
Immunofluorescence HP1/Rap1 29670078
In Vivo
In vivo

In SCID mice bearing s.c. G401 xenografts, EPZ-6438 induces tumor stasis during the administration period and produces a significant tumor growth delay with minimal effect on body weight. [1]
Animal Research Animal Models SCID mice bearing s.c. G401 xenografts.
Dosages ~500 mg/kg
Administration Oral administration

Chemical Information & Solubility

Molecular Weight 572.74 Formula

C34H44N4O4
CAS No. 1403254-99-8 SDF Download Tazemetostat (EPZ-6438) SDF
Smiles CCN(C1CCOCC1)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C4=CC=C(C=C4)CN5CCOCC5
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 100 mg/mL ( (174.59 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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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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Frequently Asked Questions

Question 1:
Could you please help test the formulation of S7128 for in vivo studies?

Answer:
We've tried some vehicles for S7128 EPZ-6438, and found it can be dissolved in 2% DMSO+30% PEG 300+5% Tween+ddH2O at 5 mg/ml as a clear solution. S7128 dissolved in 5% DMSO+0.5% CMC Na at 15 mg/ml is a suspension for oral gavage.

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