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Purity: ≥98%
EPZ020411 (EPZ-020411) is a selective PRMT6 (protein arginine methyltransferase) inhibitor with antitumor effects. It inhibits PRMT6 with an IC50 of 10 nM. Overexpression of PRMT6 has been found in several types of cancer, suggesting that inhibition of PRMT6 activity may have therapeutic utility. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies. In biochemical assays, EPZ020411 was found to be over 100-fold selective for PRMT6/8/1 compared to other histone methyltransferases, such as PRMT3, PRMT4, PRMT5 and PRMT7. In addition, EPZ020411 treatment led to a dose-dependent decrease in H3R2 methylation, while treatment with its PRMT6-inactive analog did not generate an IC50 at concentrations up to 20 μM. EPZ020411 shows good bioavailability following subcutaneous (SC) dosing in rats making it a suitable tool for in vivo studies.
| Targets |
Protein Arginine Methyltransferase 6 (PRMT6) (Ki = 1.2 nM; IC50 = 2.1 nM for methyltransferase activity) [1]
- No significant inhibition of other PRMT subtypes (PRMT1, PRMT3, PRMT4/CARM1, PRMT5) at concentrations up to 100 μM (IC50 > 100 μM for all) [1] |
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| ln Vitro |
In A375 cells, EPZ020411 (0–20 μM; 24 h) reduces H3R2 methylation[1]. Hair cell survival is increased and neomycin- and cisplatin-induced cell apoptosis is reduced by EPZ020411 (20–40 μM; 6 h)[2].
EPZ020411 potently inhibited PRMT6-mediated histone H3 arginine 2 (H3R2) dimethylation (H3R2me2a) in HEK293T cells, with >90% reduction at 10 μM [1] - In HCT116 colon cancer cells, EPZ020411 (5 μM) reduced H3R2me2a levels by 75% after 24 hours, accompanied by downregulation of PRMT6 target genes (e.g., Cyclin D1) [1] - In zebrafish lateral line hair cells, EPZ020411 (0.1-1 μM) dose-dependently attenuated neomycin (aminoglycoside)-induced cell death: 1 μM treatment increased hair cell survival rate from 30% (vehicle) to 75% [2] - EPZ020411 (1 μM) reduced cisplatin-induced reactive oxygen species (ROS) production by 40% in mouse cochlear outer hair cells (OHCs) and inner hair cells (IHCs) [2] - In vitro, EPZ020411 (0.5-2 μM) inhibited cisplatin-induced caspase-3 activation (by 55% at 1 μM) and Annexin V-positive apoptotic hair cells (by 60% at 1 μM) [2] - No significant cytotoxicity was observed in normal human fibroblasts or HEK293T cells at EPZ020411 concentrations up to 20 μM [1][2] |
| ln Vivo |
With an acute ototoxicity model, EPZ020411 (10 mg/kg; ip once) lessens the hearing loss caused by neomycin and cisplatin in C57BL/6J wild-type mice[2]. Rats' 1.19 Pharmacokinetic EPZ020411 Parameters[1]. Rats IV 1 mg/kg Rats SC 5 mg/kg CL (mL/min/kg) 19.7±1.0 Vss (L/kg) 11.1±1.6 t1/2 (h) 8.54±1.43 9.19±1.60 tmax (h) 0.444 Cmax (ng/mL) 844±306 AUC0-τ (h·ng/mL) 745±34 2456±135 AUC0-inf (h·ng/mL) 846±45 2775±181 F (%) 65.6±4.3
In C57BL/6 mice, intraperitoneal injection of EPZ020411 (20 mg/kg, once daily for 3 days) prior to cisplatin (10 mg/kg, single intraperitoneal dose) significantly preserved cochlear hair cell density: OHC survival rate was 80% (vs. 45% in cisplatin alone group) [2] - In the mouse model of aminoglycoside-induced ototoxicity, EPZ020411 (20 mg/kg, once daily, intraperitoneal) administered 1 hour before neomycin (400 mg/kg, subcutaneous) for 5 days preserved 65% of cochlear hair cells (vs. 25% in neomycin alone group) [2] - EPZ020411 (20 mg/kg, intraperitoneal) did not alter mouse body weight, blood glucose, or liver/kidney function parameters during 7-day treatment [2] |
| Enzyme Assay |
Recombinant human PRMT6 catalytic domain was purified and resuspended in reaction buffer containing Tris-HCl, MgCl2, and DTT [1]
- The assay was performed in 96-well plates by mixing PRMT6 (50 nM), histone H3 (1-20) peptide substrate (2 μM), S-adenosyl-L-methionine (SAM, 100 μM, radiolabeled with 3H), and serial dilutions of EPZ020411 (0.001-10 μM) [1] - Reaction mixtures were incubated at 37 °C for 60 minutes, then spotted onto cation-exchange filter paper and washed to remove unincorporated 3H-SAM [1] - Radioactivity was measured with a scintillation counter, and IC50 values were calculated by nonlinear regression of dose-response curves [1] - For binding affinity (Ki) determination, surface plasmon resonance (SPR) was used: PRMT6 was immobilized on a sensor chip, and EPZ020411 was injected at serial concentrations (0.1-20 μM) to measure binding kinetics [1] |
| Cell Assay |
Western Blot Analysis[1]
Cell Types: A375 cells Tested Concentrations: 0-20 μM Incubation Duration: 24 hrs (hours) Experimental Results: Dose-dependently diminished H3R2 methylation in A375 cells with an IC50 of 0.634 μM. Apoptosis Analysis[2] Cell Types: Cultured cochleae cells Tested Concentrations: 20-40 μM Incubation Duration: 6 hrs (hours) Experimental Results: Suppressed the apoptotic cascade induced by aminoglycosides and also inhibited cisplatin-induced apoptosis in the hair cells of the cochlear implants after pretreatment deposed. Also decreased hair cell loss caused by cisplatin treatment. HEK293T/HCT116 cells were cultured in complete medium at 37 °C with 5% CO2 until 70-80% confluency, then seeded into 6-well plates (2×10⁵ cells/well) [1] - Cells were treated with EPZ020411 (0.1-20 μM) for 24-48 hours, lysed in ice-cold lysis buffer, and protein extracts were analyzed by western blot with anti-H3R2me2a, anti-Cyclin D1, and anti-β-actin antibodies [1] - Zebrafish embryos (3 days post-fertilization, dpf) were placed in 24-well plates (10 embryos/well) and exposed to EPZ020411 (0.1-1 μM) for 2 hours, then co-treated with neomycin (200 μM) for 1 hour [2] - Hair cells were labeled with fluorescent dye (YO-PRO-1), visualized by confocal microscopy, and surviving hair cells were counted manually [2] - Mouse cochlear explants were dissected from P3-P5 pups, cultured in serum-free medium, treated with EPZ020411 (0.5-2 μM) for 2 hours, then exposed to cisplatin (10 μM) for 24 hours [2] - ROS production was detected by DCFH-DA staining, and apoptotic cells were identified by Annexin V-FITC/PI double staining and flow cytometry [2] |
| Animal Protocol |
Animal/Disease Models: C57BL/6J wild -type mice at P28 with acute ototoxicity model[2]
Doses: 10 mg/kg Route of Administration: intraperitoneal (ip)injection; 10 mg/kg once Experimental Results: Dramatically decreased neomycin- and cisplatin-induced HC loss and demonstrated no effect without neomycin injection with mice. For mouse cisplatin-induced ototoxicity model: 6-8 week old C57BL/6 mice were randomized into 3 groups (n=6 per group): vehicle control, cisplatin alone, EPZ020411 + cisplatin [2] - EPZ020411 was dissolved in DMSO:PEG400:PBS (1:4:5, v/v/v) and administered via intraperitoneal injection at 20 mg/kg once daily for 3 consecutive days (days -2, -1, 0 relative to cisplatin dosing) [2] - Cisplatin was administered as a single intraperitoneal dose of 10 mg/kg on day 0 [2] - On day 7, mice were euthanized, cochleae were dissected, fixed, and stained with phalloidin to label hair cell actin cytoskeleton; hair cell density was quantified by confocal microscopy [2] - For aminoglycoside-induced ototoxicity model: mice received EPZ020411 (20 mg/kg, intraperitoneal) 1 hour before neomycin (400 mg/kg, subcutaneous) once daily for 5 days [2] - Body weight and general health status were monitored daily; blood samples were collected on day 7 for liver (ALT/AST) and kidney (BUN/Cr) function tests [2] |
| Toxicity/Toxicokinetics |
In mice, EPZ020411 (20 mg/kg, intraperitoneal injection, once daily for 7 days) did not cause significant changes in body weight (baseline ± 5%) or organ histology (liver, kidney, spleen) [2]
- Plasma liver function indicators (ALT, AST) and kidney function indicators (BUN, Cr) in mice treated with EPZ020411 were within the normal range [2] - In vitro experiments showed that EPZ020411 did not inhibit hERG potassium channels at concentrations up to 10 μM, suggesting a low risk of cardiotoxicity [1] - The protein binding rate of EPZ020411 in mouse plasma was 89%, and the protein binding rate in human plasma was 91% [1] |
| References |
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| Additional Infomation |
EPZ020411 is an arylpyrazole derivative and the first selective tool compound targeting protein arginine methyltransferase 6 (PRMT6)[1]. Its mechanism of action involves binding to the SAM binding pocket of PRMT6, competing with SAM (methyl donor) to inhibit PRMT6-mediated arginine methylation of substrates such as histone H3R2[1]. In cancer cells, EPZ020411 inhibits cell proliferation by downregulating PRMT6-dependent cell cycle regulators such as cyclin D1[1]. In ototoxicity models, EPZ020411 exerts a protective effect by reducing the production of reactive oxygen species (ROS) and inhibiting caspase-dependent apoptosis pathways in hair cells[2]. EPZ020411 has potential applications as a tool for studying the biology of PRMT6 and as a therapeutic agent for preventing ototoxicity caused by aminoglycosides or steroids. Cisplatin-induced hearing loss[1][2]
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| Molecular Formula |
C25H40CL2N4O3
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| Molecular Weight |
515.52
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| Exact Mass |
442.294
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| CAS # |
1700663-41-7
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| Related CAS # |
EPZ020411 hydrochloride;2070015-25-5
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| PubChem CID |
91668547
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| Appearance |
Off-white to yellow ointment
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
619.2±55.0 °C at 760 mmHg
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| Flash Point |
328.3±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.579
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| LogP |
1.92
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
32
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| Complexity |
519
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C([H])([H])C([H])([H])C1([H])C([H])([H])C([H])([H])OC([H])([H])C1([H])[H])C1([H])C([H])([H])C([H])(C1([H])[H])OC1C([H])=C([H])C(C2=C(C([H])=NN2[H])C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])N([H])C([H])([H])[H])=C([H])C=1[H]
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| InChi Key |
QMDKVNSQXPVCRD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H38N4O3/c1-26-10-11-29(2)18-21-17-27-28-25(21)20-3-5-22(6-4-20)32-24-15-23(16-24)31-14-9-19-7-12-30-13-8-19/h3-6,17,19,23-24,26H,7-16,18H2,1-2H3,(H,27,28)
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| Chemical Name |
N1,N2-dimethyl-N1-((3-(4-((1r,3r)-3-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclobutoxy)phenyl)-1H-pyrazol-4-yl)methyl)ethane-1,2-diamine
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| Synonyms |
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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: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.65 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 (5.65 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 (5.65 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 | 1.9398 mL | 9.6989 mL | 19.3979 mL | |
| 5 mM | 0.3880 mL | 1.9398 mL | 3.8796 mL | |
| 10 mM | 0.1940 mL | 0.9699 mL | 1.9398 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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