生物活性
LY3023414是一种选择性的ATP竞争性抑制剂,抑制PI3Kα和mTOR,DNA-PK和其他I类PI3K家族成员的选择性ATP竞争性抑制剂。LY3023414对PI3Kα,PI3Kβ,PI3Kδ,PI3Kγ,DNA-PK和mTOR的IC50值分别为 6.07 nM,77.6 nM,38 nM,23.8 nM,4.24 nM和 165 nM。
在体外研究中,LY3023414能抑制PI3K下游T308位的Akt磷酸化,IC50为106nM。LY3023414抑制p70S6K对下游S6RP(pS240/244)的磷酸化,说明LY3023414能抑制整个PI3K/AKT/mTOR信号通路靶点。LY3023414 在一半的细胞系中表现出有效的单药活性,IC 50值低于122 nM。LY3023414在体内研究中,表现出较高的生物利用度,其体内半衰期为2小时。
化学数据
分子量 | 406.48 |
分子式 | C23H26N4O3 |
CAS号 | 1386874-06-1 |
纯度 | >99% |
溶解性(25°C) | DMSO: 40 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 | RKO and SK-OV-3 cells; MOLT-4 and L-363 cells; DLD-1, HCT-116, HCT-15, and NCI-H460 cells |
方法 | The CellTiter-Glo luminescent cell viability assay system is used to measure the antiproliferative effects of LY3023414 after 2 cell doublings on cells plated on plastic or incubated for 2 weeks in soft agar with a collection of standard cell lines and human patient–derived tumor xenografts passaged in nude mice. For the soft-agar assay, RKO and SK-OV-3 cells; MOLT-4 and L-363 cells; DLD-1, HCT-116, HCT-15, and NCI-H460 cells are used. These standard cell lines are genotyped by STR and matched to existing STR reference genotypes. Oncotest PDX models (including model MX1 originally derived at NCI) are characterized using the Affymetrix genome-wide human SNP Array 6.0 as well as whole-exome sequencing. Genetic identity analysis confirm that all PDX models are derived from independent patient samples. Combination studies are conducted in which LY3023414 is mixed with other therapeutic agents in fixed ratios of concentrations corresponding to the IC50 equivalents of each single agent. The combination index at 50% inhibition (CI50) is calculated. |
浓度 | |
处理时间 | |
动物实验 |
---|
动物模型 | athymic nude, CD-1 nude and NMRI athymic nude mice(Xenograft tumors) |
配制 | 1% HEC in distilled water containing 0.25% polysorbate 80 and 0.05% Dow-Corning Antifoam 1510-US |
剂量 | |
给药处理 | p.o. |
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 | 2.4601 mL | 12.3007 mL | 24.6015 mL |
5 mM | 0.492 mL | 2.4601 mL | 4.9203 mL |
10 mM | 0.246 mL | 1.2301 mL | 2.4601 mL |