生物活性
NVP-TAE684是一种有效的，选择性的ALK抑制剂，IC50为3 nM，作用于ALK比作用于InsR选择性高100倍。TAE684能阻断ALCL来源的和ALK依赖的细胞系生长，IC50分别为2和10 nM。TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3μM in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg. TAE684 potently inhibits the proliferation of Ba/F3 NPM-ALK cells with IC50 of 3 nM, without affecting the survival of Ba/F3 cells even at 1 μM. TAE684 also inhibits proliferation of NPM-ALK-expressing human ALCL cell lines including Karpas-299 and SU-DHL-1 with IC50 of 2–5 nM. Molecular modeling reveals that L258 may be one of the major kinase-selectivity determinants for TAE684. TAE684 treatment results in a rapid and sustained inhibition of phosphorylation of NPM-ALK. TAE684 induces apoptosis and G1 phase arrest in NPM-ALK-expressing Ba/F3 cells and ALCL patient cell lines. be one of the major kinase-selectivity determinants for TAE684. Neurite outgrowth induced by expression of the mALK R1279Q mutant could be completely inhibited by TAE684 at 30 nM.
化学数据
| 分子量 | 614.2 |
| 分子式 | C30H40ClN7O3S |
| CAS号 | 761439-42-3 |
| 纯度 | >98% |
| 溶解性（25°C） | DMSO ≥28 mg/mL
Ethanol ≥1.8 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 | Luciferase-expressing Karpas-299, SU-DHL-1, and Ba/F3 cells and transformed Ba/F3 stably expressing NPM-ALK, Bcr-Abl, or TEL-kinase fusion constructs. |
| 方法 | Seeding cells in 384-well plates (2.5×104cells per well) and incubating with serial dilutions of TAE684 or DMSO for 2–3 days. Using Luciferase expression as a measure of cell proliferation/survival and evaluating with the Bright-Glo Luciferase Assay System.Using XLFit software to generate IC50 values . |
| 浓度 | 1 nM-10 μM |
| 处理时间 | 2–3 days |
| 动物实验 |
|---|
| 动物模型 | Karpas-299 xenografts are established in 4- to 6-week old female Fox Chase SCIDBeige mice |
| 配制 | Resuspended in 10% 1-methyl-2-pyrrolidinone/90% polyethylene glycol 300 solution |
| 剂量 | 1, 3, and 10 mg/kg |
| 给药处理 | Once daily by oral gavage for 3 weeks |
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 | 1.6281 mL | 8.1407 mL | 16.2813 mL |
| 5 mM | 0.3256 mL | 1.6281 mL | 3.2563 mL |
| 10 mM | 0.1628 mL | 0.8141 mL | 1.6281 mL |
