生物活性
PF-03814735 is a novel, potent, orally bioavailable, reversible small-molecule Aurora kinase inhibitor with IC50 of 0.8, 5, 10 and 22 nM for Aurora 1, Aurora 2, Flt 1 and FAk, respectively. Aurora kinases are serine- threonine kinases that play essential roles in mitotic checkpoint control during mitosis. PF-03814735?possesses potential antineoplastic activity. Aurora kinase inhibitor PF-03814735 binds to and blocks Aurora kinases A and B, which may result in the prevention of cellular division and proliferation in tumor cells that overexpress these kinases. In intact cells, the preventive activity of PF-03814735 on the Aurora1 and Aurora2 kinases attenuates levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 generates a block in cytokinesis, leading to prevention of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 generates significant prevention of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral injection of PF-03814735 to mice bearing human xenograft tumors generates an attenuation in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. PF-03814735 is originally developed by Pfizer. The phase I clinical trials for the treatment of solid tumors has been completed.
化学数据
| 分子量 | 474.48 |
| 分子式 | C23H25F3N6O2 |
| CAS号 | 942487-16-3 |
| 纯度 | >98% |
| 溶解性（25°C） | DMSO |
| 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 | HCT-116 cell |
| 方法 | Growing cell lines in appropriate media and evaluating after 48 h of exposure to either PF-03814735 or vehicle, followed by cell number determination in a Coulter Counter. Proliferation (as measured by an increase in cell number) is expressed as a percent of untreated controls. To evaluate the PF-03814735 exposure time required for antiproliferative activity, culturing HL-60 cell cultures in RPMI medium supplemented with 15% heat-inactivated fetal bovine serum and exposing them to various PF-03814735 concentrations for 4, 8, 12, 24, and 48 hours, followed by a washout step and incubation with growth media without PF-03814735 for the remainder of the 72-h assay period. Evaluating continuous exposure to PF-03814735 for 72 hours . Determining cell counts by a Coulter Counter. |
| 浓度 | 300 nM |
| 处理时间 | 4, 8, 12, 24, 48, or 72 hours |
| 动物实验 |
|---|
| 动物模型 | HCT116 tumors are implanted s.c. on the right flank of nude mice. |
| 配制 | PF-03814735 is formulated as a solution in cremophor EL [cremophor/ethanol/0.9% saline (12.5%/12.5%/75%)]. |
| 剂量 | 10, 20, 30 mg/kg |
| 给药处理 | Administered orally |
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 | 2.1076 mL | 10.5379 mL | 21.0757 mL |
| 5 mM | 0.4215 mL | 2.1076 mL | 4.2151 mL |
| 10 mM | 0.2108 mL | 1.0538 mL | 2.1076 mL |
