Tazemetostat free base | CAS#1403254-99-8| EZH2 inhibitor

MedKoo Cat#: 406265 | Name: Tazemetostat free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Tazemetostat (EPZ-6438, E7438) is a potent, selective, and orally bioavailable small-molecule inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase involved in epigenetic gene silencing. It inhibits both wild-type and mutant EZH2 (e.g., Y641 and A677 mutations) with nanomolar potency—IC₅₀ values of 2.5 nM (Y641N), 11 nM (Y641F), and 4.7 nM (wild-type EZH2) in biochemical assays. In cellular models, Tazemetostat leads to a reduction in trimethylation of histone H3 at lysine 27 (H3K27me3) and induces antiproliferative effects in EZH2-mutant diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma cells. In xenograft models, oral administration of Tazemetostat significantly reduces tumor growth with favorable pharmacokinetic properties and minimal toxicity. These properties support its clinical development, and it is currently FDA-approved for certain relapsed/refractory follicular lymphomas and epithelioid sarcomas.

Chemical Structure

Tazemetostat free base

CAS#1403254-99-8 (free base)

Theoretical Analysis

MedKoo Cat#: 406265

Name: Tazemetostat free base

CAS#: 1403254-99-8 (free base)

Chemical Formula: C34H44N4O4

Exact Mass: 572.3363

Molecular Weight: 572.74

Elemental Analysis: C, 71.30; H, 7.74; N, 9.78; O, 11.17

Price and Availability

Size	Price	Availability
10mg	USD 55.00	Ready to ship
100mg	USD 150.00	Ready to Ship
200mg	USD 250.00	Ready to Ship
1g	USD 750.00	Ready to Ship
2g	USD 1,150.00	Ready to Ship
5g	USD 2,250.00	Ready to Ship
10g	USD 3,650.00	Ready to Ship

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Related CAS #

1467052-84-1 (HCl) 1467052-75-0 (HBr) 1403254-99-8 (free base) Tazemetostat mesylate

Synonym

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

IUPAC/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

InChi Key

NSQSAUGJQHDYNO-UHFFFAOYSA-N

InChi Code

InChI=1S/C34H44N4O4/c1-5-38(29-10-14-41-15-11-29)32-20-28(27-8-6-26(7-9-27)22-37-12-16-42-17-13-37)19-30(25(32)4)33(39)35-21-31-23(2)18-24(3)36-34(31)40/h6-9,18-20,29H,5,10-17,21-22H2,1-4H3,(H,35,39)(H,36,40)

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

Appearance

White to off-white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Tazemetostat (EPZ-6438) is a potent and selective EZH2 inhibitor.

In vitro activity:

First, this study examined whether pharmacological inhibition of EZH2 had anti-tumor effects on MB cells in culture and found that treatment with EPZ-6438 greatly inhibited MB cell growth in vitro (Fig. 1a). To determine whether reduced cell growth was related to cell proliferation, this study performed cell cycle analysis and found a G0/G1 block (Fig. 1b and Suppl. Fig.1). As p53 is a major regulator of cell cycle progression, this study repeated the experiment in cells stably expressing TP53-shRNA and observed neutralization of EPZ-6438’s inhibitory effect on MB cell growth (Fig. 1b, c). Since BAI1 can stabilize p53 by blocking Mdm2 and is silenced in MB cells, this studyfurther tested whether the growth inhibitory effect of EPZ-6438 is dependent upon reactivation of BAI1 tumor suppression activity and found ADGRB1-shRNAs indeed abrogated the anti-proliferative effect (Fig. 1d). Taken together, these results demonstrate that EPZ-6438 inhibits in vitro MB cancer cell growth in a BAI1/p53-dependent manner. Reference: Oncogene. 2020 Jan; 39(5): 1041–1048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780546/

In vivo activity:

This study investigated the potential for drugs that inhibit EZH2 to alter H3K27me3 in growing oocytes, primary oocytes and the developing female germline. Significantly, tazemetostat prevented H3K27me3 enrichment in growing oocytes of adult female mice in vivo, and this effect was relatively stable as H3K27me3 did not recover after 10 days of drug withdrawal. In addition, EZH2 inhibition reduced H3K27me3 in the primary oocyte pool, indicating that the lifelong primordial follicle reserve is affected by these drugs. Finally, tazemetostat severely depleted H3K27me3 in developing oocytes undergoing epigenetic reprogramming and established that once depleted, H3K27me3 did not recover in these cells within the window analysed. Combined, these findings demonstrate that EZH2 inhibitors potently reduce H3K27me3 at all stages of female germline development. Reference: Clin Epigenetics. 2018; 10: 33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836460/

	Solvent	mg/mL	mM
Solubility
	DMSO	62.5	109.12

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 572.74 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Zhang H, Zhu D, Zhang Z, Kaluz S, Yu B, Devi NS, Olson JJ, Van Meir EG. EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway. Oncogene. 2020 Jan;39(5):1041-1048. doi: 10.1038/s41388-019-1036-7. Epub 2019 Oct 3. Erratum in: Oncogene. 2019 Nov 1;: PMID: 31582835; PMCID: PMC7780546. 2. Kawano S, Grassian AR, Tsuda M, Knutson SK, Warholic NM, Kuznetsov G, Xu S, Xiao Y, Pollock RM, Smith JS, Kuntz KK, Ribich S, Minoshima Y, Matsui J, Copeland RA, Tanaka S, Keilhack H. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. PLoS One. 2016 Jul 8;11(7):e0158888. doi: 10.1371/journal.pone.0158888. Erratum in: PLoS One. 2017 Jan 13;12 (1):e0170539. PMID: 27391784; PMCID: PMC4938529. 3. Chan-Penebre E, Armstrong K, Drew A, Grassian AR, Feldman I, Knutson SK, Kuplast-Barr K, Roche M, Campbell J, Ho P, Copeland RA, Chesworth R, Smith JJ, Keilhack H, Ribich SA. Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Mol Cancer Ther. 2017 May;16(5):850-860. doi: 10.1158/1535-7163.MCT-16-0678. Epub 2017 Mar 14. PMID: 28292935. 4. Prokopuk L, Hogg K, Western PS. Pharmacological inhibition of EZH2 disrupts the female germline epigenome. Clin Epigenetics. 2018 Mar 5;10:33. doi: 10.1186/s13148-018-0465-4. PMID: 29515677; PMCID: PMC5836460.

In vitro protocol:

In vivo protocol:

1. Chan-Penebre E, Armstrong K, Drew A, Grassian AR, Feldman I, Knutson SK, Kuplast-Barr K, Roche M, Campbell J, Ho P, Copeland RA, Chesworth R, Smith JJ, Keilhack H, Ribich SA. Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Mol Cancer Ther. 2017 May;16(5):850-860. doi: 10.1158/1535-7163.MCT-16-0678. Epub 2017 Mar 14. PMID: 28292935. 2. Prokopuk L, Hogg K, Western PS. Pharmacological inhibition of EZH2 disrupts the female germline epigenome. Clin Epigenetics. 2018 Mar 5;10:33. doi: 10.1186/s13148-018-0465-4. PMID: 29515677; PMCID: PMC5836460. 3.

1: Orleni M, Beumer JH. Pharmacology and pharmacokinetics of tazemetostat. Cancer Chemother Pharmacol. 2024 May;93(5):509-517. doi: 10.1007/s00280-024-04658-4. Epub 2024 Mar 23. PMID: 38520556. 2: Anestopoulos I, Paraskevaidis I, Kyriakou S, Giova LE, Trafalis DT, Botaitis S, Franco R, Pappa A, Panayiotidis MI. 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 Feb 27;25(5):2745. doi: 10.3390/ijms25052745. PMID: 38473991; PMCID: PMC10931595. 3: Vejmelkova K, Pokorna P, Noskova K, Faustmannova A, Drabova K, Pavelka Z, Bajciova V, Broz M, Tinka P, Jezova M, Palova H, Kren L, Valik D, Slaby O, Sterba J. Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors. Sci Rep. 2023 Dec 7;13(1):21623. doi: 10.1038/s41598-023-48774-2. PMID: 38062114; PMCID: PMC10703767. 4: Amin MN, El-Far YM, El-Mowafy M, Elgaml A. Tazemetostat decreases β-catenin and CD13 protein expression in HEPG-2 and Hepatitis B virus-transfected HEPG-2 with decreased cell viability. Clin Epigenetics. 2023 Nov 8;15(1):180. doi: 10.1186/s13148-023-01593-8. PMID: 37941056; PMCID: PMC10634085. 5: Chen L, Zheng X, Liu W, Sun Y, Zhao S, Tian L, Tian W, Xue F, Kang C, Wang Y. Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR-EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer. Cancer Lett. 2023 Dec 1;578:216445. doi: 10.1016/j.canlet.2023.216445. Epub 2023 Oct 20. PMID: 37866545. 6: Chen X, Wu J, Pang G, Wei S, Wang P. Integrase Interactor 1 (INI1) Deficiency in a Lung Cancer Patient Presents Nonresponse to Immunotherapy and Tazemetostat: A Case Report. Cureus. 2023 Aug 4;15(8):e42934. doi: 10.7759/cureus.42934. PMID: 37667707; PMCID: PMC10475322. 7: Budagaga Y, Sabet Z, Zhang Y, Novotná E, Hanke I, Rozkoš T, Hofman J. Tazemetostat synergistically combats multidrug resistance by the unique triple inhibition of ABCB1, ABCC1, and ABCG2 efflux transporters in vitro and ex vivo. Biochem Pharmacol. 2023 Oct;216:115769. doi: 10.1016/j.bcp.2023.115769. Epub 2023 Aug 25. PMID: 37634597. 8: Ding N, You A, Zhao S, Yang H, Lai C, Ye F. EZH2 inhibitor Tazemetostat synergizes with JQ-1 in esophageal cancer by inhibiting c-Myc signaling pathway. Med Oncol. 2023 Aug 27;40(10):281. doi: 10.1007/s12032-023-02147-x. PMID: 37634215. 9: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. Tazemetostat. 2023 Aug 4. PMID: 37643279. 10: Chi SN, Yi JS, Williams PM, Roy-Chowdhuri S, Patton DR, Coffey BD, Reid JM, Piao J, Saguilig L, Alonzo TA, Berg SL, Ramirez NC, Jaju A, Mhlanga JC, Fox E, Hawkins DS, Mooney MM, Takebe N, Tricoli JV, Janeway KA, Seibel NL, Parsons DW. Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C. J Natl Cancer Inst. 2023 Nov 8;115(11):1355-1363. doi: 10.1093/jnci/djad085. PMID: 37228094; PMCID: PMC11009504. 11: Bekric D, Neureiter D, Ablinger C, Dobias H, Beyreis M, Ritter M, Jakab M, Bischof J, Koller U, Kiesslich T, Mayr C. Evaluation of Tazemetostat as a Therapeutically Relevant Substance in Biliary Tract Cancer. Cancers (Basel). 2023 Mar 2;15(5):1569. doi: 10.3390/cancers15051569. PMID: 36900361; PMCID: PMC10000745. 12: Chu L, Tan D, Zhu M, Qu Y, Ma X, Song BL, Qi W. EZH2 W113C is a gain-of- function mutation in B-cell lymphoma enabling both PRC2 methyltransferase activation and tazemetostat resistance. J Biol Chem. 2023 Apr;299(4):103073. doi: 10.1016/j.jbc.2023.103073. Epub 2023 Feb 27. PMID: 36858198; PMCID: PMC10066557. 13: Hou Y, Zak J, Shi Y, Pratumchai I, Dinner B, Wang W, Qin K, Weber E, Teijaro JR, Wu P. Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy. bioRxiv [Preprint]. 2023 Feb 7:2023.02.07.527459. doi: 10.1101/2023.02.07.527459. PMID: 36798389; PMCID: PMC9934551. 14: Zhang Q, Chen X, Cao J, Yang W, Wan G, Feng Q, Zhou S, Yang H, Wang N, Liu Z, Xiao H, Zhu Y, Yu L. Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer. J Med Chem. 2023 Feb 9;66(3):1725-1741. doi: 10.1021/acs.jmedchem.2c01370. Epub 2023 Jan 24. PMID: 36692394. 15: Li H, Wang YJ, Geng XN, Kang YR, Wang YL, Qiu XJ. Pharmacokinetics of Herb- Drug Interactions of Plumbagin and Tazemetostat in Rats by UPLC-MS/MS. Drug Des Devel Ther. 2022 Sep 29;16:3385-3394. doi: 10.2147/DDDT.S384156. PMID: 36199632; PMCID: PMC9529013. 16: Saleh K, Classe M, Nguyen F, Moya-Plana A, Even C. Tazemetostat for the treatment of INI-1-deficient sinonasal tumor. Eur J Cancer. 2022 Sep;172:329-331. doi: 10.1016/j.ejca.2022.06.032. Epub 2022 Jul 9. PMID: 35820243. 17: Tazemetostat Shows Antitumor Activity in Malignant Pleural Mesothelioma. Cancer Discov. 2022 Jul 6;12(7):1610. doi: 10.1158/2159-8290.CD-RW2022-096. PMID: 35621347. 18: Zauderer MG, Szlosarek PW, Le Moulec S, Popat S, Taylor P, Planchard D, Scherpereel A, Koczywas M, Forster M, Cameron RB, Peikert T, Argon EK, Michaud NR, Szanto A, Yang J, Chen Y, Kansra V, Agarwal S, Fennell DA. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2022 Jun;23(6):758-767. doi: 10.1016/S1470-2045(22)00277-7. Epub 2022 May 16. PMID: 35588752. 19: Proudman DG, Gupta D, Nellesen D, Yang J, Kamp BA, Mamlouk K, Cheson BD. Tazemetostat in relapsed/refractory follicular lymphoma: a propensity score- matched analysis of E7438-G000-101 trial outcomes. Oncotarget. 2022 May 11;13:677-683. doi: 10.18632/oncotarget.28229. PMID: 35574216; PMCID: PMC9093865. 20: Straining R, Eighmy W. Tazemetostat: EZH2 Inhibitor. J Adv Pract Oncol. 2022 Mar;13(2):158-163. doi: 10.6004/jadpro.2022.13.2.7. Epub 2022 Mar 25. PMID: 35369397; PMCID: PMC8955562.

1. Fiorentino FP, Marchesi I, Schröder C, Schmidt R, Yokota J, Bagella L. BET-Inhibitor I-BET762 and PARP-Inhibitor Talazoparib Synergy in Small Cell Lung Cancer Cells. Int J Mol Sci. 2020 Dec 16;21(24):9595. doi: 10.3390/ijms21249595. PMID: 33339368; PMCID: PMC7766292. https://www.mdpi.com/1422-0067/21/24/9595/htm 2. Yomtoubian S, Lee SB, Verma A, Izzo F, Markowitz G, Choi H, Cerchietti L, Vahdat L, Brown KA, Andreopoulou E, Elemento O, Chang J, Inghirami G, Gao D, Ryu S, Mittal V. Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer. Cell Rep. 2020 Jan 21;30(3):755-770.e6. doi: 10.1016/j.celrep.2019.12.056. PMID: 31968251. https://pubmed.ncbi.nlm.nih.gov/31968251/ 3. Mazzi S, Dessen P, Vieira M, Dufour V, Cambot M, El Khoury M, Antony-Debré I, Arkoun B, Basso-Valentina F, BenAbdoulahab S, Edmond V, Rameau P, Petermann R, Wittner M, Cassinat B, Plo I, Debili N, Raslova H, Vainchenker W. Dual role of EZH2 in megakaryocyte differentiation. Blood. 2021 Oct 28;138(17):1603-1614. doi: 10.1182/blood.2019004638. PMID: 34115825; PMCID: PMC8554649. 4. Pandey GK, Landman N, Neikes HK, Hulsman D, Lieftink C, Beijersbergen R, Kolluri KK, Janes SM, Vermeulen M, Badhai J, van Lohuizen M. Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma. Cell Rep Med. 2023 Jan 10:100915. doi: 10.1016/j.xcrm.2022.100915. Epub ahead of print. PMID: 36657447. 5. Pandey GK, Landman N, Neikes HK, Hulsman D, Lieftink C, Beijersbergen R, Kolluri KK, Janes SM, Vermeulen M, Badhai J, van Lohuizen M. Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma. Cell Rep Med. 2023 Feb 21;4(2):100915. doi: 10.1016/j.xcrm.2022.100915. Epub 2023 Jan 18. PMID: 36657447; PMCID: PMC9975229. 6. Pandey GK, Landman N, Neikes HK, Hulsman D, Lieftink C, Beijersbergen R, Kolluri KK, Janes SM, Vermeulen M, Badhai J, van Lohuizen M. Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma. Cell Rep Med. 2023 Feb 21;4(2):100915. doi: 10.1016/j.xcrm.2022.100915. Epub 2023 Jan 18. PMID: 36657447; PMCID: PMC9975229. 7. Puram SV, Mints M, Pal A, Qi Z, Reeb A, Gelev K, Barrett TF, Gerndt S, Liu P, Parikh AS, Ramadan S, Law T, Mroz EA, Rocco JW, Adkins D, Thorstad WL, Gay HA, Ding L, Paniello RC, Pipkorn P, Jackson RS, Wang X, Mazul A, Chernock R, Zevallos JP, Silva-Fisher J, Tirosh I. Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma. Nat Genet. 2023 Apr;55(4):640-650. doi: 10.1038/s41588-023-01357-3. Epub 2023 Apr 3. PMID: 37012457; PMCID: PMC10191634..