1. Epigenetics
  2. Epigenetic Reader Domain
    Histone Methyltransferase

EPZ-6438 (Synonyms: Tazemetostat; E-7438)

Cat. No.: HY-13803 Purity: 99.63%
Data Sheet SDS Handling Instructions

EPZ-6438 inhibits the activity of human PRC2-containing wild-type EZH2 with Ki of 2.5±0.5 nM.

For research use only. We do not sell to patients.
EPZ-6438 Chemical Structure

EPZ-6438 Chemical Structure

CAS No. : 1403254-99-8

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10 mM * 1 mL in DMSO $63 In-stock
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10 mg $70 In-stock
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200 mg $440 In-stock
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Customer Review

    EPZ-6438 purchased from MCE. Usage Cited in: Toxins (Basel). 2017 May 16;9(5). pii: E162.

    Cells are treated with LeTx in the presence or absence of GSK-J4 or EPZ-6438 for 48 h. H3K27me3 level is analyzed by Western blotting.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    EPZ-6438 inhibits the activity of human PRC2-containing wild-type EZH2 with Ki of 2.5±0.5 nM.

    IC50 & Target

    Ki: 2.5 nM (EZH2)[1]

    In Vitro

    EPZ-6438 inhibits EZH2 in a manner competitive with the substrate S-adenosylmethionine (SAM). EPZ-6438 inhibits EZH1, EZH2(in peptide assay), EZH2 (in nucleosome assay) with IC50of 392 nM, 11 nM and 16 nM, respectively. EPZ-6438 displays a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs tested[1].

    In Vivo

    EPZ-6438 (125 mg/kg) induces tumor stasis during the administration period and produced a significant tumor growth delay compared with vehicle after the dosing period. Measuring EPZ-6438 plasma levels either 5 min before or 3 h after dosing on day 21 reveals a clear dose-dependent increase in systemic exposure[1]. Dose-dependent target inhibition is observed in PBMCs and bone marrow from rats dosed with EPZ-6438 (orally administered, 100, 300, or 1,000 mg/kg) as measured by ELISA[2].

    Clinical Trial
    NCT Number Sponsor Condition Start Date Phase
    NCT03009344 Eisai Co., Ltd.|Eisai Inc. Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma January 10, 2017 Phase 1
    NCT02875548 Epizyme, Inc. Diffuse Large B-cell Lymphoma|Follicular Lymphoma|Malignant Rhabdoid Tumors (MRT)|Rhabdoid Tumors of the Kidney (RTK)|Atypical Teratoid Rhabdoid Tumors (ATRT)|Synovial Sarcoma|Epitheliod Sarcoma|Mesothelioma|Advanced Solid Tumors August 2016 Phase 2
    NCT03010982 Epizyme, Inc. Diffuse Large B Cell Lymphoma|Primary Mediastinal Lymphoma|Mantle-Cell Lymphoma|Follicular Lymphoma|Marginal Zone Lymphoma January 2017 Phase 1
    NCT02601950 Epizyme, Inc. Malignant Rhabdoid Tumors (MRT)|Rhabdoid Tumors of the Kidney (RTK)|Atypical Teratoid Rhabdoid Tumors (ATRT)|Selected Tumors With Rhabdoid Features|Synovial Sarcoma|INI1-negative Tumors|Malignant Rhabdoid Tumor of Ovary|Renal Medullary Carcinoma|Epithelioid Sarcoma|Any Solid Tumor With an EZH2 GOF Mutation December 2015 Phase 2
    NCT02860286 Epizyme, Inc. Mesothelioma|BAP1 Loss of Function July 2016 Phase 2
    NCT02601937 Epizyme, Inc. Rhabdoid Tumors|INI1-negative Tumors|Synovial Sarcoma|Malignant Rhabdoid Tumor of Ovary December 2015 Phase 1
    NCT03217253 National Cancer Institute (NCI) Liver Dysfunction|Metastatic Malignant Solid Neoplasm|Stage III B-Cell Non-Hodgkin Lymphoma|Stage III Hepatocellular Carcinoma AJCC v7|Stage IIIA Hepatocellular Carcinoma AJCC v7|Stage IIIB Hepatocellular Carcinoma AJCC v7|Stage IIIC Hepatocellular Carcinoma AJCC v7|Stage IV B-Cell Non-Hodgkin Lymphoma|Stage IV Hepatocellular Carcinoma AJCC v7|Stage IVA Hepatocellular Carcinoma AJCC v7|Stage IVB Hepatocellular Carcinoma AJCC v7|Unresectable Solid Neoplasm March 16, 2018 Phase 1
    NCT01897571 Epizyme, Inc. B-cell Lymphomas (Phase 1)|Advanced Solid Tumors (Phase 1)|Diffuse Large B-cell Lymphoma (Phase 2)|Follicular Lymphoma (Phase 2)|Transformed Follicular Lymphoma|Primary Mediastinal Large B-Cell Lymphoma June 2013 Phase 1|Phase 2
    NCT03213665 National Cancer Institute (NCI) Advanced Malignant Solid Neoplasm|Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor|EZH2 Gene Mutation|Histiocytosis|Loss of BRG1 Protein Expression|Loss of INI 1 Protein Expression|Low Grade Glioma|Malignant Glioma|Recurrent Childhood Central Nervous System Neoplasm|Recurrent Childhood Ependymoma|Recurrent Childhood Soft Tissue Sarcoma|Recurrent Ewing Sarcoma|Recurrent Germ Cell Tumor|Recurrent Glioma|Recurrent Hepatoblastoma|Recurrent Hodgkin Lymphoma|Recurrent Langerhans Cell Histiocyt July 24, 2017 Phase 2
    NCT03028103 Epizyme, Inc. Diffuse Large B Cell Lymphoma|Primary Mediastinal Lymphoma|Mantle Cell Lymphoma March 27, 2017 Phase 1
    NCT02220842 Hoffmann-La Roche Lymphoma December 18, 2014 Phase 1
    NCT02889523 The Lymphoma Academic Research Organisation|Epizyme, Inc. Lymphoma, Large B-Cell, Diffuse October 2016 Phase 1|Phase 2
    NCT03155620 National Cancer Institute (NCI) Advanced Malignant Solid Neoplasm|Childhood Langerhans Cell Histiocytosis|Histiocytic Sarcoma|Juvenile Xanthogranuloma|Malignant Glioma|Recurrent Central Nervous System Neoplasm|Recurrent Childhood Ependymoma|Recurrent Childhood Malignant Germ Cell Tumor|Recurrent Childhood Medulloblastoma|Recurrent Childhood Non-Hodgkin Lymphoma|Recurrent Childhood Rhabdomyosarcoma|Recurrent Childhood Soft Tissue Sarcoma|Recurrent Ewing Sarcoma|Recurrent Glioma|Recurrent Hepatoblastoma|Recurrent Langerhans Cell July 24, 2017 Phase 2
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    References
    Preparing Stock Solutions
    Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
    1 mM 1.7460 mL 8.7300 mL 17.4599 mL
    5 mM 0.3492 mL 1.7460 mL 3.4920 mL
    10 mM 0.1746 mL 0.8730 mL 1.7460 mL
    Cell Assay
    [1]

    EPZ-6438 is dissolved in DMSO and stored, and then diluted with appropriate media before use[1].

    293T (CRL-11268), RD (CRL-136), SJCRH30 (CRL-2061), A204 (HTB-82), G401 (CRL-1441), G402 (CRL-1440), KYM-1 (JCRB0627), 293T, RD, SJCRH30, A204, G401, and G402 cells are used. 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[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1][2]

    EPZ-6438 is prepared in 0.5% NaCMC plus 0.1% Tween 80 in water.

    Mice[1]
    SCID mice bearing s.c. G401 xenografts are inoculated s.c. at the right flank with G401 tumor cells (5×106 cells per mouse) in 0.2-mL mixture of base media and Matrigel for tumor development. The treatments are started when the tumor size reached 157 mm3 for the tumor efficacy study (n=16 mice per group). EPZ-6438 (125 mg/kg, 250 mg/kg, and 500 mg/kg) or vehicle (0.5% NaCMC plus 0.1% Tween 80 in water) is administered orally BID at a dose volume of 10 µL/g for either 21 or 28 d. Animal body weights are measured every day during the first week, and then twice weekly for the remainder of the study. Tumor size is measured twice weekly in two dimensions using a caliper, and the volume is expressed in cubic millimeters.
    Rat[2]
    Male and female Sprague-Dawley rats (8 weeks old) are orally treated with EPZ-6438 (100, 300, or 1,000 mg/kg) or vehicle for 28 days once a day. On day 22, the females from the highest dose group received another dose and are subsequently euthanized on day 23 approximately 29 hours after the last dose. All other animals are euthanized on day 29 approximately 29 hours after the last dose administered on day 28. At euthanasia, the full blood volume is collected, peripheral blood mononuclear cells (PBMC) are isolated, and cell pellets are frozen and stored at −80°C before analysis. A 2-mm-thick slice of skin is formalin-fixed for 24 hours and transferred to 70% ethanol. The fixed tissues are paraffin embedded. Bone marrow samples are collected from femur, tibia, and hip bones, frozen and stored at −80°C before analysis. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    572.74

    Formula

    C₃₄H₄₄N₄O₄

    CAS No.

    1403254-99-8

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    DMSO: 5.0 mg/mL (need ultrasonic)

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    Purity: 99.63%

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    Cat. No.:
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