Tazemetostat (EPZ-6438)

Catalog No.S7128 Batch:S712817

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Technical Data

Formula

C34H44N4O4

Molecular Weight 572.74 CAS No. 1403254-99-8
Solubility (25°C)* In vitro DMSO 100 mg/mL (174.59 mM)
Water Insoluble
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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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.
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 NSC-9900 or Hexadecadrol in several EZH2 mutant lymphoma cell lines. [2]

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]

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.

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 Assay:

[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 Study:

[1]

  • Animal Models

    SCID mice bearing s.c. G401 xenografts.

  • Dosages

    ~500 mg/kg

  • Administration

    Oral administration

Customer Product Validation

Data from [Data independently produced by , , Cell, 2018, 175(1):186-199]

Data from [Data independently produced by , , J Pathol, 2017, 242(3):371-383]

Data from [Data independently produced by , , Clin Epigenetics, 2018, 10(1):121]

Data from [Data independently produced by , , Oncotarget, 2016, 7(10):11194-207]

Selleck's Tazemetostat (EPZ-6438) has been cited by 149 publications

AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution [ Nature, 2024, 10.1038/s41586-024-08031-6] PubMed: 39385030
EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors [ Signal Transduct Target Ther, 2024, 9(1):2] PubMed: 38161208
Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma [ Nat Commun, 2024, 15(1):1367] PubMed: 38355622
Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-γ response pathway activation [ J Immunother Cancer, 2024, 12(10)e009590] PubMed: 39424359
Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma [ Haematologica, 2024, 109(6):1893-1908] PubMed: 38124661
C-terminal binding protein (CTBP2) is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma [ Blood Adv, 2024, bloodadvances.2023010218] PubMed: 38457926
Interferon regulatory factor 4 modulates epigenetic silencing and cancer-critical pathways in melanoma cells [ Mol Oncol, 2024, 10.1002/1878-0261.13672] PubMed: 38880659
Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells [ Int J Mol Sci, 2024, 25(5)2745] PubMed: 38473991
PDGF-BB overexpression in p53 null oligodendrocyte progenitors increases H3K27me3 and induces transcriptional changes which favor proliferation [ Neoplasia, 2024, 57:101042] PubMed: 39216363
PPARγ and C/EBPα enable adipocyte differentiation upon inhibition of histone methyltransferase PRC2 in malignant tumors [ J Biol Chem, 2024, 300(10):107765] PubMed: 39276936

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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