GSK864
目录号 : GC17809
GSK864是一种突变型isocitrate dehydrogenases 1 (mIDH1)抑制剂，对IDH1 R132H、IDH1 R132C及WT IDH1的EC50值分别为0.16μM、0.10μM和2.74μM。
Cas No.:1816331-66-4
Sample solution is provided at 25 µL, 10mM.
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GSK864 is a mutant isocitrate dehydrogenases 1 (mIDH1) inhibitor, with EC50 values of 0.16μM, 0.10μM, 2.74μM for IDH1 R132H, IDH1 R132C, and IDH1 WT, respectively [1]. GSK864 can specifically inhibit the WT IDH1, resulting in a dose-dependent decrease in the NADPH/NADP+ ratio[2]. GSK864 has been widely used in cell and animal models to inhibit the progression of acute myeloid leukemia (AML)[3].
In vitro, GSK864 treatment for 48 hours significantly inhibited the proliferation of Jurkat cells and MV4-11 cells, with IC50 values of 2μM and 8μM respectively[4]. Treatment with 15μM GSK864 for 7 days significantly inhibited the proliferation of Ovcar3 cells and increased the SA-β-Gal activity in the cells[5].
In vivo, GSK864 treatment at a dose of 150mg/kg/day for 10 days (i.p.) significantly reduced the progression of GIC-20 xenograft tumors and prolonged the survival time of mice[6]. Intraperitoneal administration of GSK864 (150mg/kg/day) for 12 days significantly reduced leukemia cells in R132H IDH1 mutant engrafted mice, and led to a slight increase in the number of huCD45+CD38+ cells[7]. GSK864 treatment (150mg/kg/day; i.p.) for 14 days significantly reduced the tumor volume in the YCC3 xenograft mouse model[8].
References:
[1] Urban D J, Martinez N J, Davis M I, et al. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays[J]. Scientific reports, 2017, 7(1): 12758.
[2] Tommasini-Ghelfi S, Murnan K, Kouri F M, et al. Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease[J]. Science advances, 2019, 5(5): eaaw4543.
[3] Kandarp J, Kloos A, Goerlich K, et al. Characterizing Secondary-Site Mutations in Isocitrate-Dehydrogenase-1 (IDH1)[J]. Blood, 2024, 144: 4139.
[4] Shait Mohammed M R, Alzahrani F, Hosawi S, et al. Profiling the effect of targeting wild isocitrate dehydrogenase 1 (IDH1) on the cellular metabolome of leukemic cells[J]. International Journal of Molecular Sciences, 2022, 23(12): 6653.
[5] Dahl E S, Buj R, Leon K E, et al. Targeting IDH1 as a prosenescent therapy in high-grade serous ovarian cancer[J]. Molecular Cancer Research, 2019, 17(8): 1710-1720.
[6] Calvert A E, Chalastanis A, Wu Y, et al. Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation[J]. Cell reports, 2017, 19(9): 1858-1873.
[7] Okoye-Okafor U C, Bartholdy B, Cartier J, et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia[J]. Nature chemical biology, 2015, 11(11): 878-886.
[8] Xu C, Ooi W F, Qamra A, et al. HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer[J]. Gut, 2020, 69(2): 231-242.
GSK864是一种突变型isocitrate dehydrogenases 1 (mIDH1)抑制剂，对IDH1 R132H、IDH1 R132C及WT IDH1的EC50值分别为0.16μM、0.10μM和2.74μM[1]。GSK864通过特异性抑制野生型IDH1，可诱导NADPH/NADP+比值呈剂量依赖性下降[2]。GSK864已广泛应用于细胞和动物模型中抑制急性髓系白血病(AML)的进展[3]。
在体外，GSK864处理48小时能显著抑制Jurkat细胞和MV4-11细胞增殖，IC50值分别为2μM和8μM[4]。使用15μM的GSK864处理Ovcar3细胞7天，可显著抑制细胞增殖并提高细胞中SA-β-半乳糖苷酶活性[5]。
在体内，每日腹腔注射150mg/kg剂量的GSK864连续10天，可显著延缓GIC-20移植瘤的进展并延长小鼠生存时间[6]。每日腹腔注射150mg/kg剂量的GSK864连续12天，能显著减少移植IDH1 R132H突变体移植小鼠体内白血病细胞数量，并轻微增加huCD45+CD38+细胞比例[7]。每日腹腔注射150mg/kg剂量的GSK864连续14天，可显著缩小YCC3移植瘤小鼠模型的肿瘤体积[8]。
| Cell experiment [1]: | |
Cell lines | Ovcar3 cells |
Preparation Method | Ovcar3 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), under a temperature of 37°C and a CO2 concentration of 5%. 1×105 cells were seeded in 6-well plates. The cells were treated with 15μM GSK864 or DMSO and cultured for 7 days. The cell proliferation and SA-β-Gal activity were analyzed. |
Reaction Conditions | 15μM; 7 days |
Applications | GSK864 treatment suppressed proliferation of Ovcar3 cells and increased SA-β-Gal activity. |
| Animal experiment [2]: | |
Animal models | CB17 SCID mice |
Preparation Method | CB17 SCID mice were intracranially injected with Luciferase-expressing GIC-20 cells (3x105 cells). Two weeks after implantation, mice were randomized into two groups based on bioluminescence. 10 mice received 150mg/kg/day GSK864 or vehicle through intraperitoneal injection for 10 days. The biological luminescence signal was used to monitor tumor growth. |
Dosage form | 150mg/kg/day for 10 days; i.p. |
Applications | GSK864 treatment significantly reduced the progression of GIC-20 xenograft tumors and prolonged the survival time of mice. |
References: | |
| Cas No. | 1816331-66-4 | SDF | |
| 化学名 | (S)-1-(4-fluorobenzyl)-N3-(4-methoxy-3,5-dimethylphenyl)-7-methyl-5-(1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3,7-dicarboxamide | ||
| Canonical SMILES | O=C(C1=NN(C2=C1CN(C[C@@]2(C(N)=O)C)C(C3=CC=CN3)=O)CC4=CC=C(C=C4)F)NC5=CC(C)=C(C(C)=C5)OC | ||
| 分子式 | C30H31FN6O4 | 分子量 | 558.6 |
| 溶解度 | DMF: 20 mg/ml,DMSO: 20 mg/ml,Ethanol: 20 mg/ml,Ethanol:PBS(pH 7.2) (1:1): 0.5 mg/ml | 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 | 1.7902 mL | 8.9509 mL | 17.9019 mL |
| 5 mM | 358 μL | 1.7902 mL | 3.5804 mL |
| 10 mM | 179 μL | 895.1 μL | 1.7902 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >98.00%
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