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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 | |
|---|---|
| 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 | |
|---|---|
| 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 |
| Related SPHK Products |
|---|
| K145 hydrochloride
K145 Hydrochloride is a selective, substrate competitive and oral inhibitor of SphK2, IC50 4.3 µM and Ki 6.4 µM. K145 hydrochloride has no activity against SphK1 and other protein kinases. K145 Hydrochloride induces apoptosis and has strong anti-tumor activity. |
| MHP
MHP (Methyl caprooyl tyrosinate), an activator of sphingosine kinase (SPHK1), can significantly increase CAMP mRNA and protein levels. MHP (Methyl caprooyl Tyrosinate) can enhance anti-microbial defense and innate immunity. |
| MP-A08
Mp-a08 is a highly selective inhibitor of ATP-competitive sphingine kinase (SPHK1) with Ki value of 6.9 μM. |
| SKI-178
SKI-178 is a potent sphingosine kinase-1 (SphK1) and SphK2 inhibitor. In acute myeloid leukemia (AML) cell lines, the IC50 range is about 500 nm-1 μM. Ski-178 induces apoptosis of human acute myeloid leukemia cells in a CDK1-dependent manner. |
| SLM6031434 hydrochloride
SLM6031434 hydrochloride is a highly selective sphingosine kinase 2 (SphK2) inhibitor with Kis of 0.4 μM, 0.5 μM, >20 μM, 22 μM for mSphK2, rSphK2, mSphK1 and rSphK1, respectively. SLM6031434 hydrochloride decrease Sphingosine 1-phosphate (S1P) levels in U937 monocytic leukemia cells. SLM6031434 hydrochloride has the potential for renal fibrosis research. |
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