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GSK-1070916

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产品编号 T6129Cas号 942918-07-2
别名 GSK-1070916A, GSK1070916

GSK-1070916 (GSK-1070916A) 是一种选择性,ATP 竞争型的极光激酶B/C 抑制剂,Ki 值分别为0.38和1.5 nM。

GSK-1070916
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GSK-1070916

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纯度: 98.51%
产品编号 T6129 别名 GSK-1070916A, GSK1070916Cas号 942918-07-2

GSK-1070916 (GSK-1070916A) 是一种选择性,ATP 竞争型的极光激酶B/C 抑制剂,Ki 值分别为0.38和1.5 nM。

规格价格库存数量
1 mg¥ 366现货
5 mg¥ 822现货
10 mg¥ 1,330现货
25 mg¥ 1,970现货
50 mg¥ 2,790现货
100 mg¥ 4,130现货
1 mL x 10 mM (in DMSO)¥ 918现货
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产品介绍

生物活性
产品描述
GSK-1070916 (GSK-1070916A) is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex. Phase 1.
靶点活性
Aurora C-INCENP:6.5 nM, Aurora B-INCENP:3.5 nM
体外活性
GSK1070916 对 Aurora B和Aurora C的 Ki值为 0.38 nM和1.5 nM。针对Aurora B和C的抑制作用是时间依赖的,其酶-抑制剂解离半寿命分别>480分钟和270分钟。此外,GSK1070916还是一种与ATP竞争的抑制剂。[1]用GSK1070916处理的人类肿瘤细胞表现出剂量依赖性地抑制Histone H3第10丝氨酸的磷酸化,这是Aurora B的特异性底物。GSK1070916还能够抑制超过100种跨越广泛肿瘤类型细胞系的肿瘤细胞增殖,EC50值均<10 nM,中值EC50为8 nM。尽管GSK1070916对增殖细胞具有强大活性,但在原代、非分裂的正常人静脉内皮细胞中观察到其活性有显著变化。此外,GSK1070916处理的细胞并不在有丝分裂中停滞,而是失败分裂成为多倍体,最终导致凋亡。[2]在另一项研究中,还报告了高染色体数与对Aurora B和C抑制的抵抗性相关,这表明具有绕过高倍体检查点机制的细胞对GSK1070916具有抵抗性。[3]
体内活性
GSK1070916(25、50或100 mg/kg)在小鼠中显示出对Aurora B特异性底物磷酸化的剂量依赖性抑制作用。该化合物在包括乳腺癌、结肠癌、肺癌和两种白血病模型在内的10种人类肿瘤异种移植模型中展示了抗肿瘤效果。[2]
激酶实验
Kinase Assay: The ability of GSK1070916 to inhibit the Aurora enzymes is measured using in vivo kinase assays. The assays measure the ability of Aurora A, Aurora B and Aurora C to phosphorylate a synthetic peptide substrate. Biotin-Ahx-RARRRLSFFFFAKKK-NH2 is used for the Aurora A–TPX2 LEADseekerTM assay and 5FAM-PKAtide is used for the IMAPTM assay for all three Aurora kinases. To take into account time-dependent inhibition of Aurora enzymes, Aurora A–TPX2, Aurora B–INCENP and Aurora C–INCENP are incubated with GSK1070916 at various concentrations for 30 min before the reactions are initiated with the addition of substrates. For the Aurora A LEADseekerTM assay, final assay conditions are 0.5 nM Aurora A–TPX2, 1 μM peptide substrate, 6 mM MgCl2, 1.5 μM ATP, 0.003 μCi/μL [γ-33P] ATP in 50 mM Hepes, pH 7.2, 0.15 mg/mL BSA, 0.01% Tween-20, 5 mM DTT and 25 mM KCl. The reactions are incubated at room temperature (25 °C) for 120 min and terminated by the addition of LEADseekerTM beads in PBS containing EDTA (final concentration 2 mg/mL beads and 25 mM EDTA). The plates are then sealed, and the beads are allowed to settle overnight. Product formation is quantified using a Viewlux Imager. For the IMAPTM assays, Aurora A–TPX2 (final concentration 1 nM), Aurora B–INCENP (final concentration 2 nM) or Aurora C–INCENP (final concentration 2.5 nM) is added to the compound-containing plates in 5 μL of buffer (25 mM Hepes, pH 7.2, for Aurora A, 25 mM Hepes, pH 7.5, for Aurora B and 20 mM Hepes, pH 7.2, for Aurora C) containing 0.15 mg/mL BSA, 0.01% Tween 20 and 25 mM NaCl. This mixture is incubated at room temperature for 30 min. To start the reaction, 5 μL of a substrate solution is added containing the same Hepes buffer as used for the pre-incubation, 25 mM NaCl, MgCl2 (2, 4 and 4 mM for Aurora A, B and C respectively), DTT (4, 4 and 2 mM for Aurora A, B and C respectively), ATP (4, 4 and 10 μM for Aurora A, B and C respectively), 200 nM 5FAM-PKAtide, 0.01% Tween 20 and 0.15 mg/mL BSA. The reactions are incubated at room temperature for 120 min for Aurora A and B and 60 min for Aurora C. These reactions are then terminated by the addition of 10 μL of 1:500 (1:600 for Aurora C) Progressive Binding Reagent in 95% Progressive Binding Buffer A and 5% Progressive Binding Buffer B. Plates are incubated at room temperature for approx. 90–120 min (time allowed for equilibrium to be reached). Plates are read in a Molecular Devices Analyst plate reader in fluorescence polarization mode.
细胞实验
Cells are plated in 96-well plates in the recommended growth media and incubated at 37 °C in 5% CO2 overnight. The following day, the cells are treated with serial dilutions of GSK1070916. At this time, one set of cells is treated with CellTiter-Glo for a time equal to 0 (T = 0) measurement. Following a 6- to 7-d incubation with compound, cell proliferation is measured using the CellTiter-Glo reagent according to the manufacture's recommended protocol. As inhibition of Aurora B induces endomitosis, the degree of which differs depending on the cell type, an extended compound treatment time is required to accurately reflect the effects on cell viability across a large panel of cell lines. For analysis of cell viability, values from wells with no cells are subtracted for background correction and the data plotted as a percent of the DMSO-treated control samples using Microsoft Excel XLfit4 software. The EC50 values represent the concentration of GSK1070916 where 50% maximal effect is observed(Only for Reference)
别名GSK-1070916A, GSK1070916
化学信息
分子量507.63
分子式C30H33N7O
CAS No.942918-07-2
SmilesCCn1cc(c(n1)-c1ccc(NC(=O)N(C)C)cc1)-c1ccnc2[nH]c(cc12)-c1cccc(CN(C)C)c1
密度1.21
储存&溶解度
存储Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice.
溶解度信息
DMSO: 102 mg/mL (200.93 mM)
Ethanol: 8 mg/mL (15.8 mM)
H2O: < 1 mg/mL (insoluble or slightly soluble)
溶液配制表
Ethanol/DMSO
1mg5mg10mg50mg
1 mM1.9699 mL9.8497 mL19.6994 mL98.4969 mL
5 mM0.3940 mL1.9699 mL3.9399 mL19.6994 mL
10 mM0.1970 mL0.9850 mL1.9699 mL9.8497 mL
DMSO
1mg5mg10mg50mg
20 mM0.0985 mL0.4925 mL0.9850 mL4.9248 mL
50 mM0.0394 mL0.1970 mL0.3940 mL1.9699 mL
100 mM0.0197 mL0.0985 mL0.1970 mL0.9850 mL

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体内实验配液计算器

请在以下方框中输入您的动物实验信息后点击计算,可以得到母液配置方法和体内配方的制备方法:
TargetMol | Animal experiments比如您的给药剂量是 10 mg/kg ,每只动物体重 20 g ,给药体积 100 μLTargetMol | Animal experiments 一共给药动物 10 只 ,您使用的配方为 5% TargetMol | reagent DMSO+ 30%PEG300+ 5%Tween 80 + 60% ddH2O. 那么您的工作液浓度为 2 mg/mL
母液配置方法: 2 mg 药物溶于 50 μLDMSOTargetMol | reagent ( 母液浓度为 40 mg/mL ), 如您需要配置的浓度超过该产品的溶解度,请先与我们联系。
体内配方的制备方法:50μLDMSOTargetMol | reagent 母液,添加 300 μLPEG300TargetMol | reagent 混匀澄清,再加 50μLTween 80, 混匀澄清,再加 600μLddH2OTargetMol | reagent 混匀澄清

以上为“体内实验配液计算器”的使用方法举例,并不是具体某个化合物的推荐配制方式,请根据您的实验动物和给药方式选择适当的溶解方案。

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