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Purity: ≥98%
GSK3326595 (EPZ015938) is a novel, potent, orally bioactive, and selective inhibitor of protein arginine methyltransferase 5 (PRMT5). It potently inhibits tumor growth in vitro and in vivo in animal models. GSK3326595 is able to halt cell proliferation and induce apoptosis in numerous solid and hematologic tumor cell lines. It has demonstrated potent in vivo anti-tumor activity in animal models. The protein arginine methyltransferases (PRMT) are a family of 11 enzymes that catalyze mono- or dimethylation of arginine residues on histones. so far PRMT inhibitors (PRMTi) are still limited to preclinical studies.
| ln Vitro |
GSK3326595 (10-100 nM, 24-72 h) inhibits the ACE2-RBD interaction, which in turn prevents SARS-CoV-2 spike pseudovirus infection of HEK-293 cells and A549 cells [1]. Peritoneal macrophages are polarized toward the M1 type that is induced by IFN-γ when exposed to GSK3326595 (100 nM, 12 h) [3]. MCL cell death is induced by GSK3326595 (0.15-10 μM, 72 h) [4].
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| ln Vivo |
In LDL receptor knockout mice, GSK3326595 (5 mg/kg, Intraperitoneal injection, three times a week for nine weeks) raises liver triglyceride levels without changing atherosclerosis [3]. Enhances resistance to programmed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) in myeloid neoplasia transgene-initiated (MYC-ON) small efficacy in murine hepatocellular carcinoma (HCC) [5]. GSK3326595 is administered orally, once daily, for two weeks.
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| Cell Assay |
Western Blot Analysis[4]
Cell Types: HEK-293T cells, A549 cells Tested Concentrations: 10 nM, 25 nM, 50 nM, 100 nM Incubation Duration: 48 h Experimental Results: Strongly inhibited ACE2-RBD interaction at low concentration. Inhibited SARS-CoV -2 Omicron and other variants Spike1 binding with ACE2. Inhibits SARS-CoV-2 spike pseudovirus infection host cells. Cell Cytotoxicity Assay[1] Cell Types: MCL cells Tested Concentrations: 0.15 μM, 0.3 μM, 0.6 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM Incubation Duration: 72 h Experimental Results: Resulted in modest growth inhibition in MCL cells. |
| Animal Protocol |
Animal/Disease Models: LDL receptor knockout mice[3]
Doses: 5 mg/kg Route of Administration: intraperitoneal (ip)injection Experimental Results: Did not alter atherosclerosis susceptibility. Increased hepatic triglyceride levels without changing the hyperlipidemia extent. Activated genes involved in fatty acid acquisition. Animal/Disease Models: myelocytomatosis transgene turned on mice[5] Doses: 25 mg/kg, 50 mg/kg Route of Administration: Oral Experimental Results: Dramatically suppressed tumor growth at 50 mg/kg. demonstrated better therapeutic efficacy at 25 mg/kg. |
| References |
[1]. Che Y, et al. Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations [J]. Blood cancer journal, 2023, 13(1): 27.
[2]. Fedoriw A, et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP loss [J]. Cancer cell, 2019, 36(1): 100-114. e25. [3]. Zhang Y, et al. PRMT5 inhibition induces pro‐inflammatory macrophage polarization and increased hepatic triglyceride levels without affecting atherosclerosis in mice [J]. Journal of Cellular and Molecular Medicine, 2023, 27(8): 1056-1068. [4]. Li Z, et al. GSK3326595 is a promising drug to prevent SARS-CoV-2 Omicron and other variants infection by inhibiting ACE2-R671 di-methylation [J]. Journal of Medical Virology, 2023, 95(1): e28158. [5]. Luo Y, et al. Myelocytomatosis-protein arginine N-methyltransferase 5 Axis defines the tumorigenesis and immune response in hepatocellular carcinoma [J]. Hepatology, 2021, 74(4): 1932-1951. |
| Molecular Formula |
C24H32N6O3
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| Molecular Weight |
452.55
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| CAS # |
1616392-22-3
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| Related CAS # |
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| SMILES |
O=C(C)N1CCC(NC2=NC=NC(C(NC[C@H](O)CN3CCC(C=CC=C4)=C4C3)=O)=C2)CC1
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| Chemical Name |
(S)-6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide
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| Synonyms |
EPZ-015938; EPZ 015938; EPZ015938; Pemrametostat; GSK3326595; GSK 3326595; GSK-3326595;
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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: ≥ 2.5 mg/mL (5.52 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (5.52 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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: 2.08 mg/mL (4.60 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Solubility in Formulation 4: 2.08 mg/mL (4.60 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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. Solubility in Formulation 5: ≥ 2.08 mg/mL (4.60 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 6: 2.2mg/mL in10% DMSO : 40% PEG300 : 5% Tween80 + : 45% saline |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2097 mL | 11.0485 mL | 22.0970 mL | |
| 5 mM | 0.4419 mL | 2.2097 mL | 4.4194 mL | |
| 10 mM | 0.2210 mL | 1.1049 mL | 2.2097 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.
Schematic representation of different DNA methyltransferase (DNMT)-inhibition approaches.Biomolecules. 2017 Mar; 7(1): 3. |
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Summary of DNMT and HMT inhibitors. The molecules labeled with a star are commercial and those marked with a cross are currently in clinical trials.Biomolecules. 2017 Mar; 7(1): 3. |
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