GSK126
(Synonyms: EZH2 inhibitor;GSK-126;GSK 126) 目录号 : GC15783
GSK126(GSK2816126A, GSK2816126)是一种高选择性EZH2甲基转移酶抑制剂，在体外的IC50为12.6~17.4nM；在体内的IC50为9.9nM。
Cas No.:1346574-57-9
Sample solution is provided at 25 µL, 10mM.
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GSK126 (GSK2816126A, GSK2816126) is a highly selective EZH2 methyltransferase inhibitor with IC50 12.6-17.4nM in vitro (MM cells), and IC50 9.9nM in vivo (Male *ApoE-/-* mice) [1,2]. Published researches show that targeting EZH2 by GSK126 is beneficial to reduces atherosclerotic plaque, and suppresses carcinogenesis, cell migration, and angiogenesis[3].
In vitro, GSK126 (5µM; 36h; 37˚C) pharmacologically inhibits EZH2, reduces lipid transportation and monocyte adhesion during atherogenesis by increasing the expression levels of ATP-binding cassette transporter A1 and suppressing vascular cell adhesion molecule 1 in human THP-1 cells[2]. GSK126 (5, 10μM; 48h) suppress colorectal cancer by regulating macrophage polarization in the tumor microenvironment in a MC38 and RAW264.7 cells based 3D culture model[4]. GSK126 (1nM-10μM; 7 days) suppress HTLV-1-infected CD4+ T cell proliferation and hyperimmune response in HTLV-1-associated myelopathy[5].
In vivo, GSK126-treated(50mg/kg/day; 10 weeks; i.p) mice showed significantly decreased atherosclerotic plaques[2]. GSK126 (100mg/kg; 1 month; i.p) inhibits the growth of colorectal cancer cells/xenografts in BALB/c nu/nu model[6]. GSK126(1nM-100μM; 3 times a week; i.p) enhances antigen presentation, antitumor immunity, and circumvents anti-PD-1 resistance in head and neck cancer C57BL/6 mice model[7].
References:
[1] Zeng, Delong et al. “Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells.” *Oncotarget* vol. 8,2 (2017): 3396-3411. doi:10.18632/oncotarget.13773
[2] Wei, Xianjing et al. “Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E-deficient mice.” *Experimental and therapeutic medicine*vol. 22,2 (2021): 841. doi:10.3892/etm.2021.10273
[3] Chen, Ya-Tian et al. “The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A.” *Cancer chemotherapy and pharmacology* vol. 77,4 (2016): 757-65. doi:10.1007/s00280-016-2990-1
[4] Li, Chen et al. “EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment.” *Frontiers in immunology* vol. 13 857808. 1 Apr. 2022, doi:10.3389/fimmu.2022.857808
[5] Koseki, Akihito et al. “EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy.” *Frontiers in microbiology* vol. 14 1175762. 12 Jun. 2023, doi:10.3389/fmicb.2023.1175762
[6] Yang, Liu et al. “PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression.” *Theranostics* vol. 11,8 3742-3759. 27 Jan. 2021, doi:10.7150/thno.53023
[7]Zhou, Liye et al. “Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research vol. 26,1 (2020): 290-300. doi:10.1158/1078-0432.CCR-19-1351
GSK126(GSK2816126A, GSK2816126)是一种高选择性EZH2甲基转移酶抑制剂，在体外的IC50为12.6~17.4nM；在体内的IC50为9.9nM[1,2]。研究表明，GSK126靶向EZH2有利于减少动脉粥样硬化斑块，抑制癌变、细胞迁移和血管生成[3]。
体外，GSK126(5µM; 36h; 37˚C)药理抑制EZH2，通过增加ATP结合盒转运蛋白A1的表达水平和抑制血管细胞粘附分子1在人THP-1细胞中减少动脉粥样硬化过程中的脂质转运和单核细胞粘附[2]。GSK126(5,10μM; 48h)在基于MC38和RAW264.7细胞的3D模型中通过调节肿瘤微环境中的巨噬细胞极化来抑制结直肠癌[4]。GSK126(1nM-10μM; 7天)抑制HTLV-1感染的CD4+ T细胞增殖和HTLV-1相关脊髓病的超免疫反应[5]。
在体内，GSK126处理(50mg/kg/天; 10周; 腹腔注射）小鼠显示动脉粥样硬化斑块明显减少[2]。GSK126(100mg/kg; 1个月; 腹腔注射）抑制BALB/c nu/nu小鼠中结直肠癌细胞/异种移植物的生长[6]。GSK126(1nM-100μM; 每周3次; 腹腔注射）在头颈癌C57BL/6小鼠模型中增强抗原呈递、抗肿瘤免疫和规避抗PD-1耐药性[7]。
| Cell experiment [1]: | |
Cell lines | human THP-1 cells |
Preparation Method | THP-1 cells were cultured in RPMI-1640 medium and treated with PMA for 48h. Subsequently, the cells were treated with GSK126 (5µM) for 36h at 37˚C in a CO2 incubator. THP-1 macrophages were then washed with PBS and cultured in serum-free RPMI-1640 medium. Following overnight fasting, the macrophages were washed with PBS again and cultured in medium with or without Ox-LDL (100µg/ml) for 48h. After incubation, macrophages were fixed in methanol at room temperature for 30min and stained with Oil Red O for 20min at room temperature and observed under a DP80 fluorescent microscope at x200 magnification. Experiments were repeated in triplicate in each group. |
Reaction Conditions | 5µM; 36h; 37˚C |
Applications | In vitro, it was found that pharmacological inhibition of EZH2 by GSK126 markedly reduced lipid transportation and monocyte adhesion during atherogenesis, predominantly through increasing the expression levels of ATP-binding cassette transporter A1 and suppressing vascular cell adhesion molecule 1 in human THP-1 cells. |
| Animal experiment [1]: | |
Animal models | Male ApoE-/- mice (n=18; age, 6-8 weeks; weight ~20g) |
Preparation Method | Male ApoE-/- mice were maintained under a specific pathogen-free environment in microisolator cages. The mice were separated into the control group (chow diet + DMSO/PBS injection), vehicle group (high-fat diet + DMSO/PBS injection) and treatment group (high-fat diet + GSK126 treatment), with six mice in each group. The mice in the control group were fed a chow diet, whereas the mice in the vehicle and treatment groups were fed a high-fat diet (21% fat, 0.15% cholesterol). All animals had free access to foods. In addition, the mice in the treatment group received a daily intraperitoneal injection of GSK126 at a dose of 50mg/kg/day (mouse body weight) for 10 weeks. The mice in the vehicle group were administered a daily intraperitoneal injection of 20% DMSO/PBS (volume, 0.1ml). Animals were sacrificed at 16-18 weeks of age. CO2 was supplied in a precisely regulated and purified form. Flow meter was used in order to maintain a gradual fill/displacement rate of 10-30% of chamber volume per min. CO2 flow was maintained for at least 1min after respiratory arrest. Following sacrifice by inhalation of CO2, the animals' heart tissue samples were collected, embedded in the OCT gel without fixation and stored at -80˚C immediately. |
Dosage form | 50mg/kg/day; 10 weeks; i.p |
Applications | In vivo, it was found that atherosclerotic plaques in GSK126-treated mice were significantly decreased when comparing with the vehicle-treated animals. These results indicated that the GSK126 has the ability to attenuate the progression of atherosclerosis by reducing macrophage foam cell formation and monocyte adhesion in cell and mouse models. |
References: | |
| Cas No. | 1346574-57-9 | SDF | |
| 别名 | EZH2 inhibitor;GSK-126;GSK 126 | ||
| 化学名 | 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-(6-piperazin-1-ylpyridin-3-yl)indole-4-carboxamide | ||
| Canonical SMILES | CCC(C)N1C=C(C2=C(C=C(C=C21)C3=CN=C(C=C3)N4CCNCC4)C(=O)NCC5=C(C=C(NC5=O)C)C)C | ||
| 分子式 | C31H38N6O2 | 分子量 | 526.67 |
| 溶解度 | ≥ 3.29 mg/mL in DMSO, <2.4 mg/mL in EtOH, <2.27 mg/mL in Water | 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 | 1.8987 mL | 9.4936 mL | 18.9872 mL |
| 5 mM | 0.3797 mL | 1.8987 mL | 3.7974 mL |
| 10 mM | 0.1899 mL | 0.9494 mL | 1.8987 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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- Purity: >98.00%
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