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    Tazemetostat (EPZ6438; E-7438)
    Tazemetostat (EPZ6438; E-7438)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0382
    CAS #: 1403254-99-8Purity ≥98%

    Description: Tazemetostat (formerly known as EPZ-6438 or E7438) is an orally bioavailable, potent, and selective EZH2 (Enhancer of Zeste-Homolog 2) inhibitor with antineoplastic activity. It inhibits EZH2 with Ki and IC50 of 2.5 nM and 11 nM in cell-free assays. Mutations within the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. Tazemetostat exhibits a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs.Tazemetostat competitively binds to the S-adenosylmethionine (SAM) binding site of EZH2 and also non-competitively binds to the binding sites of peptide or nucleosome substrate. Tazemetostat selectively inhibits EZH2 with selectivity 35-fold greater than EZH1. Study results have suggested that Tazemetostat exhibits dramatic and permanent anti-tumor activity in MRT models through synergistic effects of Tazemetostat-mediated EZH2 inhibition on several cancer pathways. 

    References: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7

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    Molecular Weight (MW)572.74
    FormulaC34H44N4O4
    CAS No.1403254-99-8
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 5 mg/mL (8.7 mM)
    Water:  <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)4% DMSO+30% PEG 300+5% Tween 80+ddH2O: 2.5 mg/mL
    Synonyms

    Tazemetostat; E7-438; E 7438; E7438; EPZ 6438; EPZ6438; EPZ-6438; 

    Chemical Name: N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide

    SMILES Code: O=C(C1=CC(C2=CC=C(CN3CCOCC3)C=C2)=CC(N(CC)C4CCOCC4)=C1C)NCC5=C(C)C=C(C)NC5=O 


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    In Vitro

    In vitro activity: 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. The antiproliferative effect of EPZ-6438 is enhanced by either prednisolone or dexamethasone in several EZH2 mutant lymphoma cell lines.


    Kinase Assay: 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 Assay: 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.

    In VivoIn 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.
    Animal modelSCID mice bearing s.c. G401 xenografts.
    Formulation & DosageDissolved in 0.5% NaCMC plus 0.1% Tween 80 in water; 500 mg/kg; Oral administration
    References

    Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Tazemetostat (EPZ-6438)

    EPZ-6438 eradicates SMARCB1-deleted MRT xenografts in SCID mice. . 2013 May 7; 110(19): 7922–7927.

    Tazemetostat (EPZ-6438)

    Effects of EPZ-6438 on cellular global histone methylation and cell viability. . 2013 May 7; 110(19): 7922–7927.

    Tazemetostat (EPZ-6438)

    EPZ-6438 induces changes in expression of SMARCB1-regulated genes and cell morphology. . 2013 May 7; 110(19): 7922–7927.


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