| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| Other Sizes |
| Targets |
EPZ011989 primarily targets EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of histone H3 at lysine 27 (H3K27). By inhibiting EZH2, EPZ011989 reduces H3K27 methylation, leading to derepression of tumor suppressor genes and inhibition of cancer cell proliferation. The compound is selective for EZH2 over EZH1 and other lysine methyltransferases. It is particularly effective against cancers with EZH2 mutations or overexpression.
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|---|---|
| ln Vitro |
EPZ-011989 trifluoroacetate inhibits both wild-type and mutant EZH2 with a Ki value of less than 3 nM[1]. EPZ-011989 trifluoroacetate has an IC50 value of 94 nM, which means it can lower cellular H3K27 methylation[1]. WSU-DLCL2 cells are resistant to proliferation when exposed to EPZ-011989 trifluoroacetate (0–10 μM; 11 days) [1].
In vitro, EPZ011989 inhibits EZH2 with a biochemical Ki of <3 nM for both mutant and wild-type EZH2. It displays 15-fold selectivity for EZH2 over EZH1. EPZ011989 reduces H3K27 methylation in cancer cells and inhibits cell proliferation with IC50 values in the nanomolar range. It induces apoptosis and cell cycle arrest in EZH2-dependent cancer cell lines. The compound is highly selective and does not affect other lysine methyltransferases. |
| ln Vivo |
Trifluoroacetate EPZ-011989 (oral; 30-1000 mg/kg; once or twice daily; for 7 or 21 days) causes strong anti-tumor action and methyl tag inhibition [1].
In vivo, EPZ011989 exhibits significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. It reduces H3K27 methylation in tumor tissues and inhibits tumor growth. The compound is orally bioavailable and has useful pharmacokinetic properties. EPZ011989 is well-tolerated at effective doses and shows robust in vivo activity. |
| Enzyme Assay |
For EZH2 methyltransferase assays, recombinant PRC2 complex or EZH2 is incubated with EPZ011989 at varying concentrations in buffer containing S-adenosylmethionine and a peptide substrate. Methylation is detected by scintillation counting or fluorescence. IC50 values are calculated from dose-response curves.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: WSU-DLCL2 Cell Tested Concentrations: 0-10 μM Incubation Duration: 11 days Experimental Results: The average minimum cytotoxic concentration (LCC) in WSU-DLCL2 cells was 208 nM. For cell-based assays, cancer cell lines are treated with EPZ011989 at serial dilutions for 72 hours. Cell viability is assessed by MTT or sulforaphane assays. H3K27 methylation is measured by Western blot. Apoptosis is assessed by caspase-3 activity or annexin V staining. |
| Animal Protocol |
Animal/Disease Models: SCID (severe combined immunodeficient) mouse [1]
Doses: 125, 250, 500, and 1000 mg/kg Route of Administration: Oral; single dose twice (two times) daily (BID) for 7 days or twice (two times) daily (BID) for 21 days Experimental Results: LCC coverage was provided for 24 hrs (hrs (hours)) (1000 mg/kg), while the 250 and 500 mg/kg doses provided 24 hrs (hrs (hours)) (1000 mg/kg) coverage for approximately 8 hrs (hrs (hours)). Complete ablation of the methyl label was observed at the end of day 7. Demonstrated potent tumor growth inhibition, diminished methyl labelling, and prolonged total and free plasma exposure. Animal/Disease Models: Rat[1] Doses: 30, 100 and 300 mg/kg Route of Administration: po (po (oral gavage)) Single Experimental Results:Dose (mg/kg) Route t1/2 (h) tmax (h) Cmax (ng/mL ) AUCinf (h*ng/mL) Time above LCC (h) 30 po 4.7 2 240 970 4 100 po 3.9 2.7 1600 5600 8 300 po 3.7 2.7 2900 10000 10 For in vivo studies, nude mice bearing human B cell lymphoma xenografts are administered EPZ011989 orally at doses ranging from 10-100 mg/kg daily. Tumor volume is measured every 2-3 days. Tumor tissues are collected for Western blot analysis of H3K27 methylation. For pharmacokinetic studies, plasma and tumor levels are quantified by LC-MS/MS. |
| References |
| Molecular Formula |
C39H53F6N5O8
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|---|---|
| Molecular Weight |
833.87
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| Exact Mass |
719.386
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| CAS # |
1598383-41-5
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| Related CAS # |
EPZ011989;1598383-40-4;EPZ011989 hydrochloride;2095432-26-9
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| PubChem CID |
118704752
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| Appearance |
Light yellow to yellow solid powder
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| tPSA |
124
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
51
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| Complexity |
1190
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
CCN(C1CCC(CC1)N(C)CCOC)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C#CCN4CCOCC4.C(=O)(C(F)(F)F)O
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| InChi Key |
JAUQBEFSKUVFDO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H51N5O4.C2HF3O2/c1-7-40(30-12-10-29(11-13-30)38(5)15-18-43-6)33-23-28(9-8-14-39-16-19-44-20-17-39)22-31(27(33)4)34(41)36-24-32-25(2)21-26(3)37-35(32)42;3-2(4,5)1(6)7/h21-23,29-30H,7,10-20,24H2,1-6H3,(H,36,41)(H,37,42);(H,6,7)
|
| Chemical Name |
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-[ethyl-[4-[2-methoxyethyl(methyl)amino]cyclohexyl]amino]-2-methyl-5-(3-morpholin-4-ylprop-1-ynyl)benzamide;2,2,2-trifluoroacetic acid
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| Synonyms |
EPZ 011989 TFA EPZ011989 TFA EPZ011989 TFA salt
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~138.92 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.47 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1992 mL | 5.9961 mL | 11.9923 mL | |
| 5 mM | 0.2398 mL | 1.1992 mL | 2.3985 mL | |
| 10 mM | 0.1199 mL | 0.5996 mL | 1.1992 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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