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    InvivoChem Cat #: V1504
    CAS #: 1415562-82-1 Purity ≥98%

    Description: PF-543 (also called PF543; PF 543; Sphingosine Kinase 1 Inhibitor II) is a novel cell-permeable and sphingosine-competitive inhibitor of SphK1 with potential antitumor activity. It inhibits inhibits SphK1 with IC50s and Ki of 2.0 nM and 3.6 nM, and exhibits >100-fold selectivity for SphK1 over the SphK2 isoform.  

    References: Biochem J. 2012 May 15;444(1):79-88.

    Related CAS#: 1706522-79-3 (HCl); 1415562-83-2 (citrate); 1415562-82-1 (free base)

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    Molecular Weight (MW)465.6
    CAS No.1415562-82-1 (free base)
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 93 mg/mL (199.7 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Other InfoChemical Name: (R)-(1-(4-((3-methyl-5-((phenylsulfonyl)methyl)phenoxy)methyl)benzyl)pyrrolidin-2-yl)methanol
    InChi Code: InChI=1S/C27H31NO4S.ClH/c1-21-14-24(20-33(30,31)27-7-3-2-4-8-27)16-26(15-21)32-19-23-11-9-22(10-12-23)17-28-13-5-6-25(28)18-29;/h2-4,7-12,14-16,25,29H,5-6,13,17-20H2,1H3;1H/t25-;/m1./s1
    SMILES Code: OC[[email protected]@H]1N(CC2=CC=C(COC3=CC(CS(=O)(C4=CC=CC=C4)=O)=CC(C)=C3)C=C2)CCC1
    SynonymsPF543; PF-543 HCl; PF543; PF 543; PF-543 hydrochloride

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    In Vitro

    In vitro activity: PF543 is a cell-permeable hydroxyl methylpyrrolidine compound that inhibits SphK-1/SphK1-catalyzed sphingosine phosphorylation in a reversible and sphingosine-competitive manner, exhibiting no affinity toward S1P receptors and much reduced inhibitory activity against Sphk2 (6.8% inhibition at 10 μM) or 46 other lipid and portein kinases (IC50 >10 μM). 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. PF-543 is 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.

    Kinase Assay: A 384-well format of the SphK enzyme assay based on separation of FITC-S1P from unreacted FITC-sphingosine substrate using a microfluidic capillary electrophoresis mobility-shift system is developed. Briefly, 3 nM SphK1–His6 is incubated with 1 μM FITC-sphingosine, 20 μM ATP and 10 μM compound (a final concentration of DMSO of 2 %) in a buffer containing 100 mM Hepes (pH 7.4), 1 mM MgCl2,0.01% Triton X-100, 10% glycerol, 100 μM sodium orthovanadate and 1 mM DTT for 1 h in a 384-well Matrical MP-101-1-PP plate. Reaction mixtures (10 μL) are quenched by the addition of 20 μL of 30 mM EDTA and 0.15% Coating Reagent-3 in 100 mM Hepes, and a small aliquot of each reaction (a few nanolitres) is analysed in the Caliper LabChip 3000 instrument under -1.5 psi (psi=6.9 kPa) pressure, a downstream voltage of -1900 V and a sip time of 0.2 s. Phosphorylated fluorescent product and unphosphorylated fluorescent substrate appeared as distinctive peaks and are quantified using the Caliper data.

    Cell Assay: In 1483 head and neck carcinoma cell cultures expressing high levels of SphK1 and with an unusually high rate of S1P production, pretreatment of PF-543 for 1 hr decreased the level of endogenous S1P by 10-fold with a proportional increase in the level of sphingosine. It indicated a significant inhibition of SphK1 BY pf-543. However, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cell cultures, despite a dramatic change in the cellular S1P/sphingosine rate.

    In VivoThe inhibitory activity of PF-543 was also examined ex vivo in human whole blood. Human whole blood with high SphK1 activity was prepared, which was able to quickly convert C17-sphingosine to C17-S1P. PF-543 treatment showed that PF-543 was a potent inhibitor of SphK1, capable of blocking >90% C17-S1P formation 
    Animal modelMice: Two month old female mice (C57BL/6 J) are injected via the tail vein with RB-005 or PF-543 (10 or 30 mg/kg) dissolved in vehicle (PBS). 20 μL blood is withdrawn via tail vein bleeds at 15 min, 30 min, 1 h, 4 h, 6 h and 24 h following drug administration. Drug concentration is determined by MS analysis
    Formulation & DosageDissolved in vehicle (PBS);  0 or 30 mg/kg; injected via the tail vein
    ReferencesBiochem J. 2012 May 15;444(1):79-88; Cell Signal. 2016 Aug;28(8):946-55.

    These protocols are for reference only. InvivoChem does not independently validate these methods.


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