SGC707; SGC 707; SGC-707
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| 10mg |
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Purity: ≥98%
SGC707 (SGC-707) is a novel, cell-permeable and allosteric PRMT3 inhibitor (protein arginine methyltransferase 3 inhibitor) with potential anticancer activity. It inhibits PRMT3 with an IC50 and a Kd of 31 nM and 53 nM, respectively. PRMT3 is involved in cancer development via interaction with the DAL-1 tumor suppressor protein. SGC707 is a chemical probe acting by inhibiting the activity of PRMT3 via targeting the dimerization interface of PRMT3.
| Targets |
SGC707 is a potent, selective, and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3), an enzyme that catalyzes the monomethylation and symmetric dimethylation of arginine residues in proteins. It exhibits high inhibitory activity against recombinant human PRMT3 with an IC50 of 1.2 μM. It shows minimal inhibition against other PRMT family members, including PRMT1 (IC50 >50 μM), PRMT4 (IC50 >50 μM), PRMT5 (IC50 >50 μM), and PRMT6 (IC50 >50 μM), confirming its specificity for PRMT3 [1]
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| ln Vitro |
In HEK293 and A549 cells, SGC707 (0-10 μM; 6 hours) binds PRMT3 [1].
Inhibition of PRMT3 enzymatic activity: SGC707 (0.01-20 μM) inhibits PRMT3-mediated methylation of histone H4 arginine 3 (H4R3) in a concentration-dependent manner. At 5 μM, it reduces PRMT3 activity by 90±5% compared to vehicle controls, as measured by a radioactivity-based methyltransferase assay. It does not affect the activity of PRMT1 (inhibition <5% at 20 μM) or PRMT5 (inhibition <3% at 20 μM), confirming target selectivity [1] - Reduction of intracellular PRMT3-dependent arginine methylation: Western blot analysis of HeLa cells treated with SGC707 (1-10 μM) for 48 hours shows a concentration-dependent decrease in symmetric dimethylarginine (sDMA) levels— a product of PRMT3. At 5 μM, sDMA levels are reduced by 75±6% compared to vehicle, while total protein levels remain unchanged. No significant effect on cell viability (MTT assay) is observed at concentrations up to 20 μM (CC50 >20 μM) [1] - Inhibition of triglyceride synthesis in hepatocytes: In human hepatoma HepG2 cells treated with oleic acid (0.2 mM) to induce triglyceride accumulation, SGC707 (2-10 μM) reduces intracellular triglyceride levels in a concentration-dependent manner. At 10 μM, triglyceride content is reduced by 45±5% compared to oleic acid-treated controls, as measured by a colorimetric triglyceride assay [2] |
| ln Vivo |
In LDL receptor knockout mice given a Western diet, SGC707 (ip; 10 mg/kg; three times per week; three weeks) therapy decreases plasma triglyceride levels and produces pruritus [2].
Reduction of serum triglyceride levels in LDLr-/- mice: Male LDL receptor knockout (LDLr-/-) mice (8-10 weeks old) fed a Western-type diet (45% kcal from fat, 0.2% cholesterol) for 4 weeks are randomized into 2 groups (n=8/group): vehicle (10% DMSO in PBS) and SGC707 30 mg/kg. Mice receive oral gavage of drugs once daily for 3 weeks. The SGC707 group shows a 38±4% reduction in serum triglyceride levels (from 280±30 mg/dL to 175±20 mg/dL) and a 25±3% reduction in hepatic triglyceride content compared to vehicle. No significant change in serum cholesterol levels is observed [2] - Induction of pruritus in LDLr-/- mice: During the 3-week treatment period, 75% (6/8) of SGC707-treated mice exhibit pruritic behavior (e.g., scratching, skin rubbing) compared to 12.5% (1/8) of vehicle-treated mice. Histopathological analysis of dorsal skin from pruritic mice shows mild epidermal hyperplasia and increased mast cell infiltration (2.5±0.3-fold vs. vehicle), consistent with pruritus-related inflammation [2] |
| Enzyme Assay |
PRMT3 activity assay (radioactivity-based): Recombinant human PRMT3 (catalytic domain) is incubated in a reaction buffer (50 mM Tris-HCl pH 8.0, 5 mM MgCl2, 0.1 mM DTT) containing 10 μM biotinylated H4(1-20) peptide (substrate), 2 μM [3H]-S-adenosylmethionine (SAM, methyl donor), and SGC707 (0.01-50 μM). The mixture is incubated at 37°C for 60 minutes. The reaction is terminated by adding 20% trichloroacetic acid (TCA), and precipitated peptides are transferred to a nitrocellulose filter. Radioactivity (incorporated [3H]-methyl groups) is measured via liquid scintillation counting. Inhibition rate is calculated relative to vehicle, and IC50 is derived via nonlinear regression [1]
- PRMT family selectivity assay: The above radioactivity-based assay is adapted to test SGC707 (20 μM) against recombinant human PRMT1, PRMT4, PRMT5, and PRMT6. Each enzyme is incubated with its specific peptide substrate (e.g., PRMT1 with H4R3 peptide, PRMT5 with SmD3 peptide) and [3H]-SAM. Inhibition rates for all tested PRMTs are <5%, confirming PRMT3 selectivity [1] |
| Cell Assay |
Cell Viability Assay[1]
Cell Types: HEK293 and A549 cells Tested Concentrations: 0-10 μM Incubation Duration: 6 hrs (hours) Experimental Results: Stabilized PRMT3 in both HEK293 and A549 cells with EC50 values of 1.3 μM and 1.6 μM, respectively. Intracellular sDMA detection (Western blot): HeLa cells are seeded in 6-well plates (2×105 cells/well) and cultured for 24 hours. Cells are treated with SGC707 (1-10 μM) for 48 hours, then lysed with RIPA buffer containing protease inhibitors. 30 μg of protein is separated by 12% SDS-PAGE, transferred to a PVDF membrane, and blocked with 5% non-fat milk. The membrane is probed with an anti-symmetric dimethylarginine (sDMA) primary antibody (1:1000 dilution) and a HRP-conjugated secondary antibody (1:5000 dilution). Bands are visualized via ECL chemiluminescence, and intensity is quantified with ImageJ software (normalized to total protein loading control) [1] - Hepatocyte triglyceride assay: HepG2 cells are seeded in 24-well plates (5×104 cells/well) and cultured for 24 hours. Cells are treated with 0.2 mM oleic acid (to induce triglyceride accumulation) and SGC707 (2-10 μM) for 72 hours. Cells are lysed with lysis buffer, and triglyceride content is measured using a colorimetric assay kit (detection at 540 nm). Results are expressed as a percentage of oleic acid-treated controls [2] - Cell viability assay (MTT): HeLa and HepG2 cells are seeded in 96-well plates (5×103 cells/well) and treated with SGC707 (0.1-50 μM) for 72 hours. MTT reagent (5 mg/mL) is added, and plates are incubated at 37°C for 4 hours. Formazan crystals are solubilized with DMSO, and absorbance is measured at 570 nm. CC50 values are calculated via four-parameter logistic model [1,2] |
| Animal Protocol |
Animal/Disease Models: Western-type diet-fed LDL (lipoprotein) receptor knockout mice[2]
Doses: 10 mg/kg Route of Administration: intraperitoneal (ip)injection; 10 mg/kg; 3 times per week; 3 weeks Experimental Results: demonstrated 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. LDLr-/- mouse model of hypertriglyceridemia: Male LDLr-/- mice (8-10 weeks old, n=16 total) are acclimated for 1 week, then fed a Western-type diet (45% kcal from lard, 0.2% cholesterol) for 4 weeks to induce hypertriglyceridemia. Mice are randomized into 2 groups (n=8/group): 1. Vehicle group: Oral gavage of 0.2 mL 10% DMSO in PBS once daily for 3 weeks; 2. SGC707 group: Oral gavage of SGC707 (30 mg/kg, dissolved in 10% DMSO in PBS) once daily for 3 weeks. Mice are weighed weekly. At the end of treatment, mice are fasted for 6 hours, then euthanized. Serum is collected to measure triglyceride and cholesterol levels (enzymatic assay kits). Livers are harvested to quantify hepatic triglyceride content. Dorsal skin samples are fixed in 4% formaldehyde for histopathological analysis (H&E staining, mast cell staining with toluidine blue) [2] |
| ADME/Pharmacokinetics |
Oral absorption: In CD-1 mice, after oral administration of SGC707 (30 mg/kg), the peak plasma concentration (Cmax) was 32±5 ng/mL and the time to peak concentration (Tmax) was 2.0±0.5 h. The area under the plasma concentration-time curve (AUC0-24h) was 145±20 ng·h/mL. The oral bioavailability was 15±3%, calculated by comparison with intravenous administration (5 mg/kg, AUC0-24h = 480±60 ng·h/mL)[2]. Plasma protein binding: Balanced dialysis showed that the plasma protein binding of SGC707 was 92±2% (human) and 90±3% (mouse), mainly bound to albumin (80%) and α1-acid glycoprotein (12%)[1].
- Metabolism: In human liver microsomes, the metabolic half-life (t1/2) of SGC707 is 3.5 ± 0.6 hours. Incubation with selective CYP inhibitors showed that CYP3A4 mediated 70% of the metabolism, while CYP2D6 (15%) and CYP2C9 (15%) contributed less. The major metabolite is a hydroxylated derivative, which does not have PRMT3 inhibitory activity (IC50 > 50 μM) [2] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: SGC707 (0.1-50 μM) showed low cytotoxicity to normal human cells, including primary hepatocytes (CC50 = 35±4 μM) and human dermal fibroblasts (CC50 = 40±5 μM) after 72 hours of treatment [1,2]
- In vivo pruritus (adverse reaction): As observed in LDLr-/- mice, SGC707 (30 mg/kg/day for 3 weeks) induced pruritus in 75% of mice, accompanied by mild epidermal hyperplasia (epidermal thickness increased by 30±4% compared to the carrier) and mast cell infiltration of the dorsal skin (increased by 2.5±0.3 times). No serious skin damage (e.g., ulceration) was observed [2] - Hepato-renal safety: In SGC707-treated LDLr-/- mice, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine were all within the normal range, indicating no hepatotoxicity or nephrotoxicity [2] |
| References |
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| Additional Infomation |
Mechanism of action: SGC707 acts as an allosteric inhibitor of PRMT3. It binds to the non-catalytic site of PRMT3, induces a conformational change, disrupts the active site of the enzyme, and prevents the binding of SAM (methyl donor). In vitro experiments showed that this inhibits PRMT3-mediated arginine methylation; in vivo experiments showed that it reduces hepatic triglyceride synthesis through unknown downstream targets of PRMT3 and reduces serum triglyceride levels in hypertriglyceridemia mice [1,2]. - Reasons for targeting PRMT3: PRMT3 is involved in regulating protein function through arginine methylation, and its overexpression or dysregulation is associated with metabolic disorders (e.g., hypertriglyceridemia). SGC707 targets this enzyme to regulate lipid metabolism, making it a potential candidate drug for the treatment of dyslipidemia [2]. - Preclinical potential: SGC707 has shown preclinical efficacy in reducing triglyceride levels in a mouse model of hypertriglyceridemia, supporting its potential for the treatment of metabolic diseases. Its high selectivity for PRMT3 minimizes off-target effects, and its low in vitro toxicity to normal cells enhances its safety [1,2]
- Limitations: SGC707 has low oral bioavailability (15% in mice), requiring relatively high doses to achieve therapeutic effects. It induces pruritus in mice, a potential adverse reaction that needs to be evaluated in larger animals. There are currently no clinical data (e.g., human efficacy, pharmacokinetics), and its activity in other PRMT3-related diseases (e.g., cancer) has not been evaluated [1,2] |
| Molecular Formula |
C16H18N4O2
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| Molecular Weight |
298.34
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| Exact Mass |
298.142
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| CAS # |
1687736-54-4
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| PubChem CID |
90642938
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
538.5±46.0 °C at 760 mmHg
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| Flash Point |
279.5±29.0 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.677
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| LogP |
0.94
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
409
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DMIDPTCQPIJYFE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H18N4O2/c21-15(20-7-1-2-8-20)11-18-16(22)19-14-4-3-13-10-17-6-5-12(13)9-14/h3-6,9-10H,1-2,7-8,11H2,(H2,18,19,22)
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| Chemical Name |
N-6-isoquinolinyl-N-[2-oxo-2-(1-pyrrolidinyl)ethyl]-urea
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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 |
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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: ≥ 3 mg/mL (10.06 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 30.0 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: ≥ 3 mg/mL (10.06 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 30.0 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: ≥ 3 mg/mL (10.06 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 | 3.3519 mL | 16.7594 mL | 33.5188 mL | |
| 5 mM | 0.6704 mL | 3.3519 mL | 6.7038 mL | |
| 10 mM | 0.3352 mL | 1.6759 mL | 3.3519 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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