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| Targets |
EPZ011989 selectively targets EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), which methylates histone H3 at lysine 27 (H3K27me3). It inhibits EZH2 with a Ki of less than 3 nM for both wild-type (WT) EZH2 and the Y646 mutant. The compound shows 15-fold selectivity over EZH1 and greater than 3000-fold selectivity over other histone methyltransferases (HMTs). This high selectivity makes EPZ011989 a valuable tool for studying EZH2-specific functions.
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| ln Vitro |
EPZ011989 inhibits both wild-type and mutant EZH2 with a Ki value of less than 3 nM[1]. At an IC50 of 94 nM, EPZ011989 lowers cellular H3K27 methylation[1]. EPZ011989 in WSU-DLCL2 (0-10 μM; 11 days)
In vitro, EPZ011989 potently inhibits EZH2 activity with a Ki of less than 3 nM for both wild-type and Y646 mutant EZH2. It demonstrates 15-fold selectivity over EZH1 and >3000-fold selectivity over other HMTs. The compound inhibits the Y641F mutant of EZH2 with an IC₅₀ of 15.0 nM and reduces H3K27me3 levels with an IC₅₀ of 110.0 nM. It exhibits antiproliferative activity against human WSU-DLCL2 cells with an IC₅₀ of 385.0 nM. The compound shows no significant inhibition of human cytochrome P450 (CYP) enzyme activities, with an IC₅₀ value greater than 100,000 nM. |
| ln Vivo |
Oral EPZ011989 (30–1000 mg/kg, single or bid; 7–21 days) has potent anti-tumor action and methyl labeling inhibition [1].
In vivo, EPZ011989 demonstrates significant tumor growth inhibition in mouse xenograft models of human B-cell lymphoma. The compound is orally bioavailable, with robust in vivo activity supporting its use as a tool compound for in vivo target validation studies. Its favorable pharmacokinetic properties and oral bioavailability make it suitable for once- or twice-daily dosing in animal models. |
| Enzyme Assay |
Non-cellular enzyme assays for EPZ011989 involve assessing its inhibition of EZH2 methyltransferase activity using purified recombinant EZH2 enzyme (wild-type or mutant). The enzyme is incubated with a peptide substrate (e.g., histone H3) and the methyl donor S-adenosylmethionine (SAM) in the presence of varying concentrations of EPZ011989. The incorporation of methyl groups into the substrate is measured using a radiometric assay with [³H]-SAM or using a luminescence-based assay (e.g., MTase-Glo™). IC₅₀ and Ki values are determined 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: demonstrated the lowest average in WSU-DLCL2 cells Cytotoxic concentration (LCC). 208 nm. In vitro cellular assays for EPZ011989 involve treating cancer cell lines (e.g., WSU-DLCL2 lymphoma cells) with the compound and assessing cell viability, proliferation, and H3K27me3 levels. Cells are treated with varying concentrations of EPZ011989 for 72-120 hours. Cell viability is measured using MTT or CellTiter-Glo® assays. H3K27me3 levels are assessed by Western blotting using a methylation-specific antibody or by using an ELISA-based assay. The inhibition of H3K27me3 is correlated with the compound's antiproliferative effects. |
| 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 In vivo animal experiments with EPZ011989 are conducted in mouse xenograft models of human B-cell lymphoma. Tumor-bearing mice are treated with EPZ011989 via oral gavage at doses ranging from 100-300 mg/kg. Tumor growth inhibition is monitored by caliper measurements. At study termination, tumors are collected for assessment of H3K27me3 levels by immunohistochemistry or Western blotting. Pharmacokinetic studies characterize absorption, distribution, and systemic exposure. |
| ADME/Pharmacokinetics |
EPZ011989 has a molecular weight of 605.81 and a molecular formula of C₃₅H₅₁N₅O₄. It is a solid powder with a purity of 99.45%. The compound is soluble in DMSO (3.8 mg/mL). It is typically stored as a powder at -20°C for up to 3 years or in solvent at -80°C for up to 1 year. The compound is stable under recommended storage conditions.
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| Toxicity/Toxicokinetics |
EPZ011989 is a research compound for laboratory use only and is not approved for human therapeutic use. In preclinical studies, it has been generally well-tolerated at therapeutic doses. As an EZH2 inhibitor, it may have effects on gene expression in normal tissues. Standard laboratory safety precautions should be followed when handling the compound. It may cause skin, eye, and respiratory irritation.
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| References | |
| Additional Infomation |
EPZ011989 (CAS 1598383-40-4) is a potent, selective, and orally bioavailable EZH2 inhibitor with a Ki of less than 3 nM for EZH2 wild-type and Y646 mutant. It shows 15-fold selectivity over EZH1 and >3000-fold selectivity over other HMTases. EPZ011989 demonstrates significant tumor growth inhibition in mouse xenograft models of human B-cell lymphoma. The compound is available from various commercial suppliers for research applications.
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| Molecular Formula |
C35H51N5O4
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| Molecular Weight |
605.82
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| Exact Mass |
605.394
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| Elemental Analysis |
C, 69.39; H, 8.49; N, 11.56; O, 10.56
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| CAS # |
1598383-40-4
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| Related CAS # |
EPZ011989 hydrochloride;2095432-26-9;EPZ011989 trifluoroacetate;1598383-41-5
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| PubChem CID |
73670548
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
756.7±60.0 °C at 760 mmHg
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| Flash Point |
411.4±32.9 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.596
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| LogP |
1.34
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
44
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| Complexity |
1110
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NCC1=C(C)C=C(C)NC1=O)C2=CC(C#CCN3CCOCC3)=CC(N(CC)[C@H]4CC[C@H](N(CCOC)C)CC4)=C2C
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| InChi Key |
XQFINGFCBFHOPE-WXUXXXNLSA-N
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| InChi Code |
InChI=1S/C35H51N5O4/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/h21-23,29-30H,7,10-20,24H2,1-6H3,(H,36,41)(H,37,42)/t29-,30-
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| Chemical Name |
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-morpholinoprop-1-yn-1-yl)benzamide
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| Synonyms |
EPZ-011989 EPZ011989 EPZ 011989.
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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 |
| 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 (~165.07 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.13 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 (4.13 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 (4.13 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 | 1.6507 mL | 8.2533 mL | 16.5066 mL | |
| 5 mM | 0.3301 mL | 1.6507 mL | 3.3013 mL | |
| 10 mM | 0.1651 mL | 0.8253 mL | 1.6507 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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