GSK3326595 (EPZ015938) (Synonyms: EPZ015938) |
| رقم الكتالوجGC32693 |
GSK3326595 (EPZ015938) (EPZ015938) هو مثبط قوي وانتقائي وقابل للعكس لبروتين أرجينين ميثيل ترانسفيراز 5 (PRMT5) مع IC50 من 6.2 نانومتر.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1616392-22-3
Sample solution is provided at 25 µL, 10mM.
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GSK3326595 (EPZ015938) is an orally active, effective, and selective inhibitor of protein arginine methyltransferase 5 (PRMT5) [1]. PRMT5 is an enzyme that methylates arginine in a protein crucial for tumor growth and development [2]. GSK3326595 can inhibit the proliferation of cancer cells and can be used in the research of relapsed/refractory mantle cell lymphoma [3-4].
In vitro, GSK3326595 (100nM; 12h) treatment induces M1-type polarization in peritoneal macrophages by inhibiting PRMT5 [5]. GSK3326595 (0 - 10μM; 3, 5 days) treatment significantly inhibits the proliferation and PRMT5 activity of B16 tumor cells and T cells [6].
In vivo, GSK3326595 (5mg/kg/day; three times a week for 9 weeks; i.p.) treatment significantly increases the levels of triglycerides and fatty acid synthase (FASN) transcripts in the liver of high cholesterol-low density lipoprotein (LDL) receptor knockout mice without affecting atherosclerosis [5]. GSK3326595 (50, 100mg/kg/day; 2 weeks) oral treatment can significantly reduce tumor multiplicity, liver weight, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the MYC-ON model mice [7].
References:
[1] Castillo-Aguilera O, Depreux P, Halby L, Arimondo PB, Goossens L. DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge. Biomolecules. 2017;7(1):3. Published 2017 Jan 5.
[2] Siu L L, Rasco D W, Vinay S P, et al. METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours[J]. Annals of Oncology, 2019, 30: v159.
[3] Gerhart, S.V., Kellner, W.A., Thompson, C., et al. Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci. Rep. 8(1), 9711 (2018)
[4] Vieito M, Moreno V, Spreafico A, et al. Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in advanced solid tumors[J]. Clinical Cancer Research, 2023, 29(18): 3592-3602.
[5] Zhang Y, Verwilligen R A F, Van Eck M, 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.
[6] Chen S, Hou J, Jaffery R, et al. MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors[J]. Journal for immunotherapy of cancer, 2024, 12(9): e009600.
[7] Luo Y, Gao Y, Liu W, Yang Y, Jiang J, Wang Y, Tang W, Yang S, Sun L, Cai J, Guo X, Takahashi S, Krausz KW, Qu A, Chen L, Xie C, Gonzalez FJ. Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma. Hepatology. 2021 Oct;74(4):1932-1951.
| Cell experiment [1]: | |
Cell lines | Peritoneal macrophages |
Preparation Method | Peritoneal macrophages were pooled together and plated in 12-well plates at a concentration of one million cells per ml in Dulbecco's Modified Eagle Medium (DMEM), containing 10% fetal bovine serum, penicillin/streptomycin and L-glutamine. After allowing the cells to attach to the culture plate for 4h (5% CO2 and 36°C), cells were washed with PBS, and exposed to 0.1% DMSO or 100μM GSK3326595 dissolved in 0.1% DMSO and in the presence of PBS as control, 1ng/mL LPS, or 100ng/mL IFN-gamma. Each condition was tested in 6 independent wells (n = 6 replicates). After 12h, cell media were collected for cytokine detection by ELISA. Cells were lysed in guanidine thiocyanate (GTC) for further mRNA expression analysis. |
Reaction Conditions | 100nM; 12h |
Applications | Treatment with GSK3326595 inhibits PRMT5, thereby inducing M1-type polarization in peritoneal macrophages through IFN-γ stimulation. |
| Animal experiment [1]: | |
Animal models | Low-density lipoprotein (LDL) receptor knockout mice (on a C57BL6/J background) |
Preparation Method | Ten-week-old male LDL receptor knockout mice (on a C57BL6/J background) were fed a Western-type diet containing 0.25% cholesterol and 15% cocoa butter (SDS) to induce the development of atherosclerotic lesions. The mice were randomly allocated to two different treatment groups receiving intraperitoneal injections of either the control solvent DMSO (100μL 10% DMSO in PBS, N = 12) or GSK3326595 (0.125mg in 100μL 10% DMSO in PBS, ~5mg/kg based on body weight at start of the experiment, N = 15) three times per week for altogether 9 weeks. For sacrifice, mice were anaesthetised through a subcutaneous injection with 100–150μL of a ketamine (100mg/kg), xylazine (12.5mg/kg), and atropine (125μg/kg) mixture. Subsequently, orbital blood was collected and a whole-body perfusion was performed using PBS. Organs were excised and parts were fixed for 24h in a 3.7% formalin solution for subsequent histological analysis or stored at −20°C for biochemical analysis. |
Dosage form | 5mg/kg/day; three times a week for 9 weeks; intraperitoneally |
Applications | Treatment with GSK3326595 significantly increased the levels of liver triglycerides and fatty acid synthase (FASN) transcripts in LDL receptor knockout mice without affecting atherosclerosis. |
References: | |
| Cas No. | 1616392-22-3 | SDF | |
| المرادفات | EPZ015938 | ||
| Canonical SMILES | O=C(C)N1CCC(NC2=NC=NC(C(NC[C@H](O)CN3CCC(C=CC=C4)=C4C3)=O)=C2)CC1 | ||
| Formula | C24H32N6O3 | M.Wt | 452.55 |
| الذوبان | DMSO : ≥ 30 mg/mL (66.29 mM) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.2097 mL | 11.0485 mL | 22.097 mL |
| 5 mM | 441.9 μL | 2.2097 mL | 4.4194 mL |
| 10 mM | 221 μL | 1.1049 mL | 2.2097 mL |
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Quality Control & SDS
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- Purity: >99.00%
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Average Rating: 5 (Based on Reviews and 1 reference(s) in Google Scholar.)
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