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.
Cell Experiment | |
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Cell lines | 1483, A549, LN229, Jurkat, U937, MCF-7 |
Preparation method | 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. |
Concentrations | ~1 μM |
Incubation time | 7 days |
Animal Experiment | |
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Animal models | Female C57BL/6 J mice (7-12 week-old) with hypoxic-induced pulmonary arterial hypertension |
Formulation | dissolved in vehicle (20% (2-Hydroxypropyl)-β-cyclodextrin in phosphate buffered saline (PBS)) |
Dosages | 1 mg/kg |
Administration | Intraperitoneal injection; every second day; for 21 days |
Molecular Weight | 502.07 |
Formula | C27H32ClNO4S |
CAS Number | 1706522-79-3 |
Solubility (25°C) | DMSO ≥ 60 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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