EPZ-6438EZH2 inhibitor,potent and selective CAS# 1403254-99-8 |
Quality Control & MSDS
3D structure
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Number of papers citing our products
| Cas No. | 1403254-99-8 | SDF | Download SDF |
| PubChem ID | 66558664 | Appearance | Powder |
| Formula | C34H44N4O4 | M.Wt | 572.74 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Tazemetostat; E-7438 | ||
| Solubility | DMSO : ≥ 25 mg/mL (43.65 mM) 0.1 M HCL : 14.29 mg/mL (24.95 mM; ultrasonic and adjust pH to 5 with HCl) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide | ||
| SMILES | CCN(C1CCOCC1)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C4=CC=C(C=C4)CN5CCOCC5 | ||
| Standard InChIKey | NSQSAUGJQHDYNO-UHFFFAOYSA-N | ||
| Standard InChI | 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) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | EPZ-6438 is a potent and selective inhibitor of EZH2 with Ki and IC50 values of 2.5 nM and 11 nM, respectively. | |||||
| Targets | EZH2 | |||||
| IC50 | 11 nM (Ki=2.5 nM) | |||||
| Cell experiment [1]: | |
| Cell lines | SMARCB1-deficient MRT cells |
| Preparation method | Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
| Reacting condition | 4-7 days |
| Applications | EPZ-6438 induces a reduction of global H3K27Me3 level in a concentration-dependent manner. In addition, EPZ-6438 leads to a substantial antiproliferative effects as IC50 values within nanomolar range. Treatment of EPZ-6438 results in expression of CD133, DOCK4, and PTPRK and up-regulates CDKN1A and CDKN2A and BIN1in a time-dependent manner. |
| Animal experiment [2]: | |
| Animal models | SCID mice bearing EZH2-mutant lymphoma xenografts. |
| Dosage form | 3 times daily every 8 hours, 2 times a day every 12 hours, or once a day schedules for either 7 or 28 days by oral gavage. |
| Application | EPZ-6438 dose-dependently causes a reduction of tumor H3K27Me3 levels (EC50 =23 nmol/L). EPZ-6438 also shows a remarkable antitumor effects in a dose dependent manner with 2 cycles of 7-day on/7-day off and 21-day on/7-day off schedules. All EPZ-6438 dose groups except the lowest one leads to complete tumor regressions. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: 1. Knutson SK, Warholic NM, Wigle TJ et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7. 2. Knutson SK, Kawano S, Minoshima Y et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54. | |
EPZ-6438 Dilution Calculator
EPZ-6438 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.746 mL | 8.73 mL | 17.4599 mL | 34.9199 mL | 43.6498 mL |
| 5 mM | 0.3492 mL | 1.746 mL | 3.492 mL | 6.984 mL | 8.73 mL |
| 10 mM | 0.1746 mL | 0.873 mL | 1.746 mL | 3.492 mL | 4.365 mL |
| 50 mM | 0.0349 mL | 0.1746 mL | 0.3492 mL | 0.6984 mL | 0.873 mL |
| 100 mM | 0.0175 mL | 0.0873 mL | 0.1746 mL | 0.3492 mL | 0.4365 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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EPZ-6438 is a potent and bio-available inhibitor of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2) catalyzing the methylation of lysine 27 of histone H3 (H3K27), that inhibits the activity of human PRC2-containing wild-type EZH2 with a value of inhibition constant Ki of 2.5 nM. EPZ-6438 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. EPZ-6438 selectively inhibits EZH2 with selectivity 35-fold greater than EZH1. Study results have suggested that EPZ-6438 exhibits dramatic and permanent anti-tumor activity in MRT models through synergistic effects of EPZ-6438-mediated EZH2 inhibition on several cancer pathways.
Reference
Sarah K. Knutson1, Natalie M. Warholic, Tim J. Wigle, Christine R. Klaus, Christina J. Allain, Alejandra Raimondi, Margaret Porter Scott, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon, Roy M. Pollock, Kevin W. Kuntz, and Heike Keilhack. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 2013; 110(19): 7922-7927
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Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma.[Pubmed:24563539]
Mol Cancer Ther. 2014 Apr;13(4):842-54.
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. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. Although both compounds are similar with respect to their mechanism of action and selectivity, EPZ-6438 possesses superior potency and drug-like properties, including good oral bioavailability in animals. Here, we characterize the activity of EPZ-6438 in preclinical models of NHL. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent manner in both EZH2 wild-type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) leads to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of EZH2-mutant NHL xenograft-bearing mice with EPZ-6438 causes dose-dependent tumor growth inhibition, including complete and sustained tumor regressions with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 days after stopping compound treatment in two EZH2-mutant xenograft models. These data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers.
No Significant Cytotoxic Effect of the EZH2 Inhibitor Tazemetostat (EPZ-6438) on Pediatric Glioma Cells with Wildtype Histone 3 or Mutated Histone 3.3.[Pubmed:27135271]
Klin Padiatr. 2016 Apr;228(3):113-7.
BACKGROUND: Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) belong to the most aggressive cancers in children with poor prognosis and limited therapeutic options. Therapeutic targeting of epigenetic proteins may offer new treatment options. Preclinical studies identified Enhancer of Zeste Homolog 2 (EZH2) within polycomb repressor complex 2 (PRC2) as a potential epigenetic anti-tumor target in adult GBM cells but similar inhibition studies in pediatric GBM/DIPG were still missing. Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome and was shown to influence EZH2 function. PATIENTS, MATERIALS AND METHODS: The present study investigated the correlation of expression of EZH2 and other PRC2 genes (EZH1, SUZ12, EED) with overall survival of pediatric GBM patients and the cytotoxic impact of EZH2 inhibition by the novel agent Tazemetostat in pediatric GBM/DIPG cells harboring either a H3.3 mutation or a H3 wildtype. RESULTS: EZH2 gene expression does not correlate with survival of pedHGG patients, and EZH2 inhibition does not induce significant cytotoxicity in pedHGG cells independently of H3.3 mutations. DISCUSSION AND CONCLUSION: We suggest that EZH2 inhibition might not offer an effective single agent treatment option for paedHGG patients. However, the therapeutic efficacy in combination with cytotoxic and/or other epigenetically active agents still has to be elucidated.
Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program.[Pubmed:27555605]
Pediatr Blood Cancer. 2017 Mar;64(3).
BACKGROUND: Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2 and currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors. PROCEDURES: Tazemetostat was tested against the Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using a dose of 400 mg/kg administered twice daily by oral gavage for 28 days. H3K27me3:H3 ratios were determined in control and treated tumors. RESULTS: Tazemetostat induced significant differences in event-free survival (EFS) distribution compared with control in nine of 30 (30%) of the xenografts studied. Significant differences in EFS distribution were observed in five of seven (71%) rhabdoid tumor xenograft lines compared with four of 23 (17%) nonrhabdoid xenograft lines (chi-square [chi(2) ] test P = 0.006). Tazemetostat induced tumor growth inhibition meeting criteria for intermediate and high EFS treated-to-control (T/C) activity in two of 25 (8%) and one of 25 (4%) xenografts, respectively. Intermediate and high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (three of five rhabdoid tumor vs 0 of 22 nonrhabdoid tumors (chi(2) test P < 0.001). One rhabdoid tumor xenograft (G401) showed stable disease. For one rhabdoid tumor (G401), delayed tumor regression to tazemetostat was noted following 1 week of tumor growth. Tazemetostat induced significant reduction of H3K27me3 levels in the majority of tumors compared with controls. CONCLUSIONS: Tazemetostat demonstrated significant antitumor activity in rhabdoid tumor models but showed no consistent activity against any other histology. Tazemetostat reduced H3K27me3 levels irrespective of tumor response. Further preclinical testing to evaluate tazemetostat in combination with other anticancer agents is warranted.
