GNE-317
目录号 : GC17338
A dual PI3Kα and mTOR inhibitor
Cas No.:1394076-92-6
Sample solution is provided at 25 µL, 10mM.
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GNE-317 is a potent inhibitor of PI3K [1].
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are a series of enzymes and play an important role in cell growth, proliferation, differentiation, survival, motility and intracellular trafficking.
In the GL261 cell line, GNE-317 showed cytotoxic activity [2].
In mouse brain, GNE-317(50 mg/kg) significantly inhibited pAkt, p4EBP1 and pS6 by 80%, 84%, and 92% respectively, which were downstream markers of the PI3K/mTOR pathway. In U87, GS2 and GBM10 tumor-bearing mice, GNE-317 inhibited tumor growth by 90%, 50% and a survival benefit, respectively [1]. In C57B6/J mice inoculated with GL261-GFP-Luc cells, the concentrations of GNE-317 in the normal brain, tumor core and rim were not significantly different. In tumor-bearing mice, GNE-317 significantly reduced the levels of p-AktSer473, p-S6Ser235/236 and p-4EBP1Thr37/46 within the tumor [2]. In U87 and GS2 glioblastoma multiforme (GBM) models, GNE-317 was uniformly distributed in the brain. The brain-to-plasma ratios for GNE-317 were greater than 1, in agreement with the brain penetration properties of GNE-317 [3].
References:
[1]. Salphati L, Heffron TP, Alicke B, et al. Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. Clin Cancer Res, 2012, 18(22): 6239-6248.
[2]. Becker CM, Oberoi RK, McFarren SJ, et al. Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. Neuro Oncol, 2015, pii: nov081.
[3]. Salphati L, Shahidi-Latham S, Quiason C, et al. Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging. Drug Metab Dispos, 2014, 42(7): 1110-1116.
Cell experiment: | GL261 is an aggressive C57BL/6J-derived glioma line. This cell line is transfected with both green fluorescent protein (GFP) and luciferase (Luc) from separate plasmids. The resultant monoclonal GL261-GFP-Luc cells are maintained in Dulbecco's modified Eagle's medium supplemented with 10% FBS and Penicillin/Streptomycin (100 U/mL) and cultured at 5% oxygen. Cell selection used 4 mg/mL Puromycin and 4 mg/mL G418. Cellular viability assays are set up in a 96-well format with 2000 cells plated per well in the culture conditions. Cells are incubated in the presence of drug or vehicle for 48 hours, and viability was assessed by MTS assay. Absorbance at 490 nm is used to determine viability and at 650 nm to account for background using a Synergy Mx automated plate reader. Numerical values from drug-treated wells are normalized to the values of vehicle-treated wells to yield percent survival[1]. |
Animal experiment: | Mice[1] GL261-GFP-Luc cells are implanted into 7-week-old C57BL/6J mice. When tumors reach 5e7 photons/s/cm2/sr (radiance), animals are orally administered the maximum tolerated dose of GDC-0980 (7.5 mg/kg), GNE-317 (30 mg/kg) or vehicle once a day for 3 days. The maximum tolerated doses are defined as the greatest dose that could be administered to mice with <10% drop in bodyweight. Even at these different doses, both doses provide similar plasma concentrations and thus the same overall systemic exposure. At 1 or 6 hours after the third dose, mice are euthanized with carbon dioxide and perfused with 30 mL PBS. With the aid of GFP goggles, brains are dissected into tumor core, tumor rim, and normal brain tissue. Tissue samples and blood are processed, and tissue specimens from each group are analyzed for drug concentrations using LC-MS/MS. |
References: [1]. Salphati L, et al. Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging. Drug Metab Dispos. 2014 Jul;42(7):1110-6. | |
| Cas No. | 1394076-92-6 | SDF | |
| 化学名 | 5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine | ||
| Canonical SMILES | COC1(COC1)C2=C(C)C3=C(S2)C(N4CCOCC4)=NC(C5=CN=C(N)N=C5)=N3 | ||
| 分子式 | C19H22N6O3S | 分子量 | 414.48 |
| 溶解度 | Soluble in DMSO | 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 | 2.4127 mL | 12.0633 mL | 24.1266 mL |
| 5 mM | 0.4825 mL | 2.4127 mL | 4.8253 mL |
| 10 mM | 0.2413 mL | 1.2063 mL | 2.4127 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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