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PF-543 HCl

Cat. No. M10599
PF-543 HCl Structure
Synonym:

PF-543 HCl; PF543 hydrochloride

Size Price Availability Quantity
5mg USD 90  USD90 In stock
10mg USD 135  USD135 In stock
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Quality Control & Documentation
Biological Activity

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.

Protocol (for reference only)
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
Chemical Information
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
Conversion of different model animals based on BSA (PMID: 27057123)
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.

References

[1] Masakazu Hamada, et al. Cell Death Discov. Induction of autophagy by sphingosine kinase 1 inhibitor PF-543 in head and neck squamous cell carcinoma cells

[2] Neil MacRitchie, et al. Cell Signal. Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension

[3] Mark E Schnute, et al. Biochem J. Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1

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Keywords: PF-543 HCl, PF-543 HCl; PF543 hydrochloride supplier, SPHK, inhibitors, activators


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