生物活性
Miransertib（ARQ 092）是一种有效的选择性和变构型 Akt 抑制剂，对 Akt1，Akt2，Akt3 的 IC50 分别为 2.7 nM，14 nM 和 8.1 nM。
In vitro: ARQ-092 demonstrates high enzymatic potency against Akt1, Akt2 and Akt3, as well as potent cellular inhibition of Akt activation and the phosphorylation of the downstream target PRAS40. ARQ-092 shows strong affinity for un-phosphorylated fulllength Akt1 and potently inhibited the phosphorylated form of full-length Akt isoforms. In a large panel of cell lines derived from various tumor types, ARQ-092 shows potent anti-proliferative activity in cell lines containing PIK3CA/PIK3R1 mutations compared to those with wild-type (wt) PIK3CA/PIK3R1 or PTEN loss. ARQ-092 shows excellent inhibition of p-Akt (S473) and p-Akt (T308) in both AN3CA and A2780 cells.
In vivo: ARQ-092 (po at 100 mg/kg, iv at 5 mg/kg) in a mouse pharmacokinetic study shows an oral bioavailability of 23%. ARQ-092 results in 99%, 95% and 58% reductions in p-Akt (S473), p-Akt (T306) and p-PRAS40 (T246), respectively, after tumor-bearing mice are treated with 100 mg/kg po. The inhibition of phosphorylation is sustained at eight hours. The plasma concentration of ARQ-092 at one hour is 2.1 μM and decreased to 0.26 μM at 8 hours, while in the tumor, the concentration is 21.0 μM at one hour and 9.6 μM at 8 hours. Treatment of the SHP2Y279C/+mice with ARQ-092 normalizes the hypertrophic cardiomyopathy (HCM) phenotype as early as 2 weeks following treatment, with levels comparable to those in SHP2+/+at this time point.
化学数据
| 分子量 | 432.52 |
| 分子式 | C27H24N6 |
| CAS号 | 1313881-70-7 |
| 纯度 | >99% |
| 溶解性（25°C） | DMSO ≥ 10 mg/mL |
| 储存和运输条件 | 固体粉末： -20°C 冷藏长期储存
常温运输及临时存放 |
实验操作 来自于公开的文献，仅供相同实验参考（如实验材料、目的不同，请参考其他文献）
| 细胞实验 |
|---|
| 细胞系 | AN3CA and A2780 cells |
| 方法 | AN3CA and A2780 cells are obtained from the ATCC. AN3CA cells are cultured in DMEM, and A2780 cells are cultured in RPMI supplemented with 10% FBS, 100 units/mL Penicillin, 100 μg/mL Streptomycin, and 2 mM Glutamine at 37 °C under 5% CO2. Cells are plated in 96-well plates at 2,000-10,000 cells/well, cultured for 24 h, and treated with the test compound for 72 h at a final DMSO concentration no greater than 0.5% v/v. PMS stock reagent (0.92 mg/mL in DPBS) is diluted 20-fold in MTS stock reagent (2 mg/mL in DPBS), and this MTS/PMS mixture is diluted 5-fold into each well of the 96-well plate. The plates are incubated for 3-4 h, and the absorbance of formazan is measured at 490 nm. The data are normalized to the untreated controls, the dose-response curves are fit to a four-parameter logistic equation, and the IC50 values are determined. All IC50 values reported are the geometric mean of at least two independent determinations. |
| 浓度 | final DMSO concentration no greater than 0.5% v/v |
| 处理时间 | 72 h |
| 动物实验 |
|---|
| 动物模型 | SHP2Y279C/+mice |
| 配制 | dissolved in 0.01 M phosphoric acid (vehicle) at a concentration of 20 mg/mL and filter sterilized |
| 剂量 | 100 mg/kg body weight |
| 给药处理 | oral gavage |
不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）
| 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。
储备液配制
以下数据基于产品分子量，对于特殊产品，请参照COA中的储备液配制条件和说明进行操作。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.312 mL | 11.5602 mL | 23.1203 mL |
| 5 mM | 0.4624 mL | 2.312 mL | 4.6241 mL |
| 10 mM | 0.2312 mL | 1.156 mL | 2.312 mL |
