GSK3326595 (EPZ015938)
(Synonyms: EPZ015938) 目录号 : GC32693
GSK3326595 (EPZ015938) 是一种具有口服活性的、有效的、选择性protein arginine methyltransferase 5（PRMT5）抑制剂。
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.
GSK3326595 (EPZ015938) 是一种具有口服活性的、有效的、选择性protein arginine methyltransferase 5（PRMT5）抑制剂 [1]。PRMT5是一种对肿瘤生长和发展至关重要的蛋白质中的精氨酸甲基化的酶 [2]。GSK3326595能够抑制癌细胞增殖，可用于复发/难治性套细胞淋巴瘤的研究 [3-4]。
在体外，GSK3326595（100nM; 12h）处理通过抑制PRMT5使腹膜巨噬细胞引发IFN-γ诱导的M1型极化 [5]。GSK3326595（0-10μM; 3, 5 days）处理能够显著抑制B16肿瘤细胞和T细胞的增殖和PRMT5活性 [6]。
在体内，GSK3326595（5mg/kg/day; three times a week for 9 weeks; i.p.）治疗显著增加了高胆固醇血症低密度脂蛋白（LDL）受体敲除小鼠的肝脏甘油三酯和脂肪酸合酶（FASN）转录物水平而不影响动脉粥样硬化 [5]。GSK3326595（50, 100mg/kg/day; 2 weeks）口服治疗可显著降低髓细胞增生启动（MYC-ON）模型小鼠的肿瘤多重性，肝脏重量以及血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平 [7]。
| 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 | |
| 别名 | EPZ015938 | ||
| Canonical SMILES | O=C(C)N1CCC(NC2=NC=NC(C(NC[C@H](O)CN3CCC(C=CC=C4)=C4C3)=O)=C2)CC1 | ||
| 分子式 | C24H32N6O3 | 分子量 | 452.55 |
| 溶解度 | DMSO : ≥ 30 mg/mL (66.29 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
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- Purity: >99.00%
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