GSK1070916是一种可逆的，ATP竞争性的Aurora B/C抑制剂，IC50为3.5 nM/6.5 nM，比作用于紧密相关的Aurora A-TPX2复合体选择性高100倍以上。
别名：GSK-1070916A
GSK1070916 is a novel, highly potent and selective Aurora B/C kinases ATP competitive inhibitor with an EC50 of <10 nM. The protein kinases, Aurora A, B, and C have critical roles in the modulation of mitosis and are frequently overexpressed or amplified in human tumors. Human tumor cells treated with GSK1070916 revealed dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B kinase. Moreover, GSK1070916 supprresses the proliferation of tumor cells. GSK1070916 displays dose-dependent inhibition of phosphorylation of an Aurora B–specific substrate in mice and consistent with its broad cellular activity, possesses antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models. In another study, GSK1070916 selectively prevents AurB-INCENP (Ki=0.38 nM) and AurC-INCENP (Ki=1.5 nM) over AurA-TPX2 (target protein for Xenopus kinesin-like protein 2) (Ki=490 nM). Suppression of AurB-INCENP and AurC-INCENP is time-dependent, with an enzyme-inhibitor dissociation half-life of more than 480 min and 270 min respectively.
| 体外实验* | |
|---|---|
| 细胞系 | SW48, Colo 201, SW480, WiDr, Colo205, RKO E6, RKO, LoVo, HCT-116, SW620, HT29, W1417, DLD-1, HCT-8, Colo 320HSR, Hep-3B, OVCAR-3, MEC-1 cells |
| 方法 | Plating cells in 96-well plates in the recommended growth media and incubated at 37 °C in 5% CO2 overnight. The following day, treating the cells with serial dilutions of GSK1070916. At this time, treating one set of cells with CellTiter-Glo for a time equal to 0 (T = 0) measurement. Following a 6- to 7-d incubation with compound, using the CellTiter-Glo reagent to measure cell proliferation 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 |
| 浓度 | 0-15 mM |
| 处理时间 | 6-7 days |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 体内实验* | |
|---|---|
| 动物模型 | Mice tumor xenograft models (A549, SW620, HCT116, H460, MCF-7, HL60, K562, Colo205) |
| 配制 | 2% Cremophor EL, 2% N,N-dimethylacetamide, and 96% acidified water (pH 5.0) |
| 剂量 | 25, 50, or 100 mg/kg |
| 给药处理 | Administered via i.p. once daily |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 分子量 | 507.63 |
| 分子式 | C30H33N7O |
| CAS号 | 942918-07-2 |
| 溶解性（25°C） | DMSO 100 mg/mL |
| 储存条件 |
粉末型式 -20°C 3年；4°C 2年 溶于溶剂 -80°C 6个月；-20°C 1个月 |
| 运输方式 | 冰袋运输，根据产品的不同，可能会有相应调整。 |
*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.9699 mL | 9.8497 mL | 19.6994 mL |
| 5 mM | 0.394 mL | 1.9699 mL | 3.9399 mL |
| 10 mM | 0.197 mL | 0.985 mL | 1.9699 mL |
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 | |
| 重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| 体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km 系数 | 3 | 6 | 12 | 8 | 5 | 20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
| 其他相关的Aurora Kinase产品 |
|---|
| Aurora Kinases-IN-4
Aurora Kinases-IN-4 是一种共价 ATP 竞争性 aurora kinase A 抑制剂 (IC50: 1.7 nM)。 |
| Derrone
Derrone 是一种戊烯基异黄酮，是 Aurora 激酶抑制剂，其对 Aurora B 和 Aurora A 的 IC50 值分别为 6 和 22.3 μM。Derrone 显示出抗肿瘤活性。 |
| CD532 hydrochloride
CD532 hydrochloride 是一种有效的 Aurora A 激酶抑制剂，IC50 值为 45 nM。CD532 hydrochloride 具有阻断 Aurora A 激酶活性和驱动 MYCN 降解的双重作用。CD532 hydrochloride 还可以直接与 AURKA 相互作用并诱导整体构象转变。CD532 hydrochloride 可用于癌症的研究。 |
| Aurora kinase inhibitor-2
Aurora kinase inhibitor-2 是一种选择性和 ATP 竞争性的 Aurora 激酶抑制剂，对 Aurora A 和 Aurora B 的 IC50 分别为 310 nM 和 240 nM。 |
| AAPK-25
AAPK-25 是一种有效选择性的 Aurora/PLK 激酶双重抑制剂，具有抗肿瘤活性。AAPK-25 可引起有丝分裂延迟并阻滞前中期细胞，通过生物标志物组蛋白 H3Ser10 磷酸化反应，随后细胞凋亡激增。AAPK-25 靶向 Aurora-A, -B, -C 的 Kd 值为 23 nM-289 nM，靶向 PLK-1, -2, -3 的 Kd 值为 55-456 nM。 |
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