| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
SMYD3 3 nM (IC50)
The molecular target of EPZ031686 is the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase that catalyzes the di- and tri-methylation of histone H3 at lysine 4 (H3K4me2/3), a mark associated with active gene transcription. The compound is a potent inhibitor of SMYD3, with a biochemical IC50 of 3 nM. It displays less than 30% inhibition against 16 other histone methyltransferase targets at 10 uM, demonstrating its high selectivity. |
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| ln Vitro |
In vitro, EPZ031686 potently inhibits SMYD3 enzyme activity with an IC50 of 3 nM in a biochemical assay. It also demonstrates cellular activity with an IC50 of 36 nM in cell-based assays, indicating effective cell permeability and target engagement. By inhibiting SMYD3, it reduces H3K4me2/3 levels and the expression of downstream genes, leading to its potential anti-proliferative effects in cancer cells that are dependent on SMYD3 activity.
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| ln Vivo |
After oral dosing in mice, EPZ031686 (1-50 mg/mL; po and iv; Male CD-1 mice) exhibits good bioavailability[1].
In vivo, EPZ031686 is orally active and has been evaluated for its pharmacokinetic properties in male CD-1 mice. Following oral dosing, the compound exhibits good bioavailability. Its oral activity makes it a valuable tool for conducting in vivo efficacy studies in mouse xenograft models to evaluate the anti-tumor potential of SMYD3 inhibition for cancer research. |
| Enzyme Assay |
A standard cell-free HTRF (Homogeneous Time-Resolved Fluorescence) assay is used. It involves incubating purified recombinant SMYD3 enzyme with a biotinylated histone H3 peptide (H3K4me0), S-adenosyl-L-methionine (SAM) as a methyl donor, and a specific antibody against the methylated product (H3K4me3). The assay detects the methylated product using a donor-fluorophore (anti-biotin-Eu) and acceptor-fluorophore (anti-H3K4me3-d2). The compound is added to the reaction to determine its IC50.
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| Cell Assay |
In a cellular assay, cancer cell lines (e.g., those dependent on SMYD3) are treated with serial dilutions of EPZ031686 (e.g., from 1 nM to 10 uM) for 48-72 hours. Cell viability is measured using a luminescence-based CellTiter-Glo assay to determine the cellular IC50. Target engagement is confirmed by Western blot analysis of cell lysates to measure the reduction in global H3K4me3 levels after compound treatment.
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| Animal Protocol |
While the provided summary does not include a detailed in vivo efficacy study protocol, the pharmacokinetic study serves as a precursor. Male CD-1 mice are administered EPZ031686 intravenously (i.v.) and orally (p.o.) at defined doses (e.g., 1 mg/kg i.v., 5 mg/kg and 50 mg/kg p.o.). Blood samples are collected at multiple time points post-dose, and plasma concentrations are analyzed by LC-MS/MS to determine the compound's PK parameters, including bioavailability, clearance, and half-life.
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| ADME/Pharmacokinetics |
Pharmacokinetic analysis in male CD-1 mice shows that EPZ031686 is orally bioavailable. Following intravenous administration (1 mg/kg), the clearance (CL) is 27 mL/min/kg and volume of distribution (Vss) is 2.3 L/kg. After oral administration (5 mg/kg), it reaches peak plasma concentration (Cmax) at 0.89 hours (tmax), with an AUC of 1281 ng-h/mL. The oral bioavailability (F) is calculated to be approximately 53% at the 5 mg/kg dose, indicating good systemic exposure.
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| Toxicity/Toxicokinetics |
Specific preclinical toxicology data for EPZ031686 is not described in the provided summaries. As a research tool, its safety profile is likely under investigation. The compound's high degree of selectivity for SMYD3 over a panel of 16 other histone methyltransferases suggests a potentially reduced risk of off-target toxicities, which is a favorable feature for a drug discovery tool.
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| References | |
| Additional Infomation |
SMYD3 is frequently overexpressed in various cancers, including colorectal, breast, and hepatocellular carcinomas, making it a potential therapeutic target. EPZ031686 is a highly potent and selective chemical probe for dissecting the biology of SMYD3. Its good oral bioavailability allows for in vivo efficacy studies, enabling researchers to validate the role of SMYD3 in tumorigenesis. It remains in the preclinical research phase and is not approved for human use.
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| Molecular Formula |
C26H34CLF3N4O4S
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|---|---|
| Molecular Weight |
591.09
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| Exact Mass |
590.194
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| CAS # |
2095161-11-6
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| PubChem CID |
118946372
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.603
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| LogP |
3.44
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
1000
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1C[C@H]2CC(C[C@@H]1N2S(=O)(=O)CC3CCN(CC3)CCCC(F)(F)F)NC(=O)C4=C(C=C5C(=C4)CC(=O)N5)Cl
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| InChi Key |
OTEIUEJPHNOGBG-IHWFROFDSA-N
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| InChi Code |
InChI=1S/C26H34ClF3N4O4S/c27-22-14-23-17(11-24(35)32-23)10-21(22)25(36)31-18-12-19-2-3-20(13-18)34(19)39(37,38)15-16-4-8-33(9-5-16)7-1-6-26(28,29)30/h10,14,16,18-20H,1-9,11-13,15H2,(H,31,36)(H,32,35)/t18?,19-,20+
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| Chemical Name |
6-chloro-2-oxo-N-[(1S,5R)-8-[[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methylsulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,3-dihydroindole-5-carboxamide
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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: 35 mg/mL (59.21 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 10 mg/mL (16.92 mM) in 30% PEG300 70% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
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. Solubility in Formulation 2: ≥ 1.75 mg/mL (2.96 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 17.5 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. View More
Solubility in Formulation 3: ≥ 1.75 mg/mL (2.96 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. Solubility in Formulation 4: ≥ 1.75 mg/mL (2.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 17.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6918 mL | 8.4589 mL | 16.9179 mL | |
| 5 mM | 0.3384 mL | 1.6918 mL | 3.3836 mL | |
| 10 mM | 0.1692 mL | 0.8459 mL | 1.6918 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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