PF-543 HCl 是一种有效的,选择性的,可逆和鞘氨醇竞争性的 SPHK1 抑制剂,IC50 为 2 nM,Ki 为 3.6 nM。PF-543 hydrochloride 对 SPHK1 的选择性是 SPHK2 的 100 倍以上。PF-543 HCl可诱导细胞凋亡、坏死和自噬。
别名:PF-543 HCl; PF543 hydrochloride
PF-543 hydrochloride is a potent, selective, reversible and sphingosine-competitive SPHK1 inhibitor with an IC50 of 2 nM and a Ki of 3.6 nM. PF-543 hydrochloride is >100-fold selectivity for SPHK1 over SPHK2. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. In the SphK1-overexpression 1483 head and neck carcinoma cells, PF-543 decreases the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. PF-543 binds SphK1 reversibly (k off t1/2=8.5 min) and with high affinity and the binding constant (Kd) is 5 nM. PF543 had no effect on the proliferation and survival of 1483, A549, LN229, Jurkat, U937 and MCF-7 cells, despite a dramatic change in the cellular S1P/sphingosine ratio.
In vivo, administration of 10 mg/kg PF-543 for 24 h to mice induces a decrease in SK1 expression in pulmonary vessels.
体外实验* | |
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细胞系 | 1483, A549, LN229, Jurkat, U937, MCF-7 |
方法 | 1483 cells were cultured in DMEM/Ham’s F-12, A549 and LN229 cells were cultured in DMEM, Jurkat and U937 cells were cultured in RPMI 1640, and MCF-7 cells were cultured in Eagle’s MEM (minimal essential medium) with 0.01 mg/ml insulin. All media were supplemented with L-glutamine, Gentamicin and 10% FBS (or 0.5% FBS as indicated). The cells were grown in 96-well plates in 100 μl of medium with PF-543 or DMSO vehicle (0.01%) at 37 ◦C in an humidified incubator in the presence of 5% CO2. The cell growth and viability was measured using the CellTiter-Glo® Assay (Promega) by quantifying luminescence proportional to the amount of ATP present according to the manufacturer’s protocol. |
浓度 | ~1 μM |
处理时间 | 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* | |
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动物模型 | Female C57BL/6 J mice (7-12 week-old) with hypoxic-induced pulmonary arterial hypertension |
配制 | dissolved in vehicle (20% (2-Hydroxypropyl)-β-cyclodextrin in phosphate buffered saline (PBS)) |
剂量 | 1 mg/kg |
给药处理 | Intraperitoneal injection; every second day; for 21 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。
分子量 | 502.07 |
分子式 | C27H32ClNO4S |
CAS号 | 1706522-79-3 |
溶解性(25°C) | DMSO ≥ 60 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 |
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1 mM | 1.9918 mL | 9.9588 mL | 19.9175 mL |
5 mM | 0.3984 mL | 1.9918 mL | 3.9835 mL |
10 mM | 0.1992 mL | 0.9959 mL | 1.9918 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。
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