Tazemetostat (EPZ-6438)

Catalog No.S7128 Synonyms: E7438

For research use only.

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

CAS No. 1403254-99-8

Selleck's Tazemetostat (EPZ-6438) has been cited by 88 publications

Purity & Quality Control

Choose Selective Histone Methyltransferase Inhibitors

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

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 prednisolone or dexamethasone in several EZH2 mutant lymphoma cell lines. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human HeLa cells NGHBVI9HfW6ldHnvckBie3OjeR?= NFLrbXQ4OiCq M1ezbGlvcGmkaYTpc44hd2ZiRWrINkBqdiCqdX3hckBJ\UyjIHPlcIx{KGG|c3Xzd4VlKGG|IILl[JVkfGmxbjDpckBJO0t{N33lN{Bt\X[nbIOgbY5kfWKjdHXkJIZweiB5MjDodpMh[nliRVzJV2EhdWW2aH;kMEBKSzVyPUCuNFIh|ryPLh?= MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPjF6OUC3PEc,OjZzOEmwO|g9N2F-
Sf9 M{DJVGZ2dmO2aX;uJIF{e2G7 NF:2cXMzKGh? MoTjTY5pcWKrdHnvckBw\iCqdX3hckBPNXSncn3pcoFtKEircz30ZYdo\WRiRWrINk9ndGGpLYTh[4dm\CCHRVSvV3VbOTJxQVXCVFIwWkKDUES4JGE3PzeJIH31eIFvfCBqMjD0c{BmdmRicnXzbYR2\XNrIHX4dJJme3OnZDDpckBj[WO3bH;2bZJ2eyCrbn\lZ5Rm\CCVZkmgbY5{\WO2IHPlcIx{KHW|aX7nJIhqe3SxbnWgTFMhMDFidH:gOVAhemW|aXT1[ZMqNUeJSzDhd{B{fWK|dILheIUh[W[2ZYKgNkBpenNiaX6gdJJme2WwY3Wgc4YhW0GPIHL5JIZtNCCLQ{WwJF0hOC5yMESg{txONg>? MVO8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR3Nke5OUc,Ojl2NU[3PVU9N2F-
KARPAS422 NHTyPJJCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBie3OjeR?= NVrSb2NrOyC2bzC0JIRigXNidYCgeI8hOTRiZHH5dy=> M{PxWmFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iS1HSVGFUPDJ{IHPlcIx{KGijcnLvdolv\yCvb37vZYxt\WyrYzDZOlQyViCHWliyJI12fGG2aX;uJIF{e2W|c3XkJIF{KHKnZIXjeIlwdiCrbjDj[YxtKH[rYXLpcIl1gSCvZXHzeZJm\CCndnXyfUA{KHSxIESg[IF6eyC3cDD0c{AyPCCmYYnzJIJ6KEKnY3vtZY4hS2:3bITldk1j[XOnZDDt[ZRpd2RuIFnDOVAhRSByLkCxNkDPxE1w MXu8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQDB7MkG1OUc,OjhyOUKxOVU9N2F-
Pfeiffer M3P4e2N6fG:2b4jpZ4l1gSCjc4PhfS=> NGC1ZVU2KGSjeYO= NFftWlFEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBR\mWrZn\ldkBk\WyuczDhd5Nme3OnZDDhd{Bl\WO{ZXHz[UBqdiClZXzsJJZq[WKrbHn0fUBi\nSncjC1JIRigXNiYomgR4VtdFSrdHXyMWdtdyC{ZXHn[Y51KGKjc3XkJIx2dWmwZYPj[Y5k\SCjc4PhfUwhUUN3MDC9JFAvODN6IN88UU4> MVe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR3Nke5OUc,Ojl2NU[3PVU9N2F-
G401 NIX2WnRHfW6ldHnvckBie3OjeR?= NG\xeXM1QCCq NFTNcXJKdmirYnn0bY9vKG:oIFXFSEBqdiCqdX3hckBIPDBzIHPlcIx{KGG|c3Xzd4VlKGG|IILl[JVkfGmxbjDpckBodG:kYXygTFNMOjevZUOgcIV3\WxiYX\0[ZIhPDhiaILzJIJ6KEWOSWPBMEBKSzVyIE2gNE4xPCEQvF2u NHr2W2E9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OEC5NlE2PSd-MkiwPVIyPTV:L3G+
G401 NXPSSGFYTnWwY4Tpc44h[XO|YYm= NYTQTXRqPCCq NWrOU|J1UW6qaXLpeIlwdiCxZjDt[ZRpgWy2cnHud4ZmemG|ZTDhZ5Rqfmm2eTDv[kBGYkh{IHnuJIh2dWGwIFe0NFEh[2WubIOgZZN{\XO|ZXSgZZMhUDONMkegeJJqdWW2aInsZZRqd25iYX\0[ZIhPCCqcoOgZpkhTUyLU1GsJGVEPTBiPTCwMlIh|ryPLh?= NHL1NY49[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{Nke2PVI4QCd-Mk[3OlkzPzh:L3G+
Pfeiffer MX\BcpRqfHWvb4KgZZN{[Xl? NGHPcoQyODBibXevb4c> M3nHdlIxKGSjeYO= MWXBcpRqfHWvb4KgZYN1cX[rdImgZYdicW6|dDDoeY1idiCSZnXp[oZmeiClZXzsd{B5\W6xZ4Lh[pRm\CCrbjDheIh6dWmlIH71[IUhdW:3c3WgZZN{\XO|ZXSgZZMhfHWvb4Kg[5Jwf3SqIHnubIljcXSrb36gZZQhOTByIH3nM4toNCCybzDx[EBi\G2rbnnzeIVz\WRiZn;yJFIxKGSjeYOgcYVie3W{ZXSgeJdq[2VicHXyJJdm\Wt? MWi8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR3Nke5OUc,Ojl2NU[3PVU9N2F-
Assay
Methods Test Index PMID
Western blot EZH2 ; H3K27me3 26360609 29670078
Immunofluorescence HP1/Rap1 29670078
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]

Protocol (from reference)

Kinase Assay:[1]
  • 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:[1]
  • 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.
Animal Research:[1]
  • Animal Models: SCID mice bearing s.c. G401 xenografts.
  • Dosages: ~500 mg/kg
  • Administration: Oral administration

Solubility (25°C)

In vitro

DMSO 5 mg/mL warmed
(8.72 mM)
Water Insoluble
Ethanol Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
5% DMSO+40% PEG 300+5% Tween 80+50% ddH2O
For best results, use promptly after mixing.

0.625mg/mL

Chemical Information

Molecular Weight 572.74
Formula

C34H44N4O4

CAS No. 1403254-99-8
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CCN(C1CCOCC1)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C4=CC=C(C=C4)CN5CCOCC5

In vivo Formulation Calculator (Clear solution)

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Molarity Calculator

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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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