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PF543 HCl (PF-543; PF 543; Sphingosine Kinase 1 Inhibitor II), the hydrochloride salt of PF-543, is a novel cell-permeable and sphingosine-competitive SphK1 inhibitor 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.
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| ln Vitro |
At nM concentrations, PF-543 (10-1000 nM; 24 hours; PASM cells) treatment eliminates SK1 expression[2]. Treatment of PASM cells with PF-543 (0.1-10 μM) for 24 hours causes caspase-3/7 activity[2]. With an IC50 of 1.0 nM, PF-543 suppresses the production of C17-S1P in 1483 cells[1]. In 1483 cells, PF-543 inhibits SphK1, leading to a dose-dependent decrease in the intracellular concentration of S1P (EC50 = 8.4 nM) and an increase in the intracellular concentration of sphingosine. Following a one-hour treatment with 200 nM PF-543, the amount of endogenous S1P in 1483 cells is reduced tenfold, leading to a corresponding increase in the level of sphingosine[1].
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| ln Vivo |
Treatment with PF-543 (1 mg/kg; intraperitoneal injection; every other day; for 21 days; female C57BL/6 J mice) decreases right ventricular hypertrophy but has no effect on vascular remodelling. Antioxidant nuclear factor Nrf-2 expression is upregulated and p53 expression is downregulated as a result of the protection[2]. Blood samples are given to mice i.p. at 10 mg/kg or 30 mg/kg of PF-543 for a duration of 24 hours. The T1/2 is 1.2 hours. Mice given 10 mg/kg PF-543 for 24 hours experience a reduction in SK1 expression in their pulmonary vessels[2].
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| Cell Assay |
Western Blot Analysis[2]
Cell Types: Human pulmonary arterial smooth muscle (PASM) cells Tested Concentrations: 10 nM, 100 nM, 1000 nM Incubation Duration: 24 hrs (hours) Experimental Results: Abolished SK1 expression at nM concentrations. Apoptosis Analysis[2] Cell Types: Human pulmonary arterial smooth muscle (PASM) cells Tested Concentrations: 0.1 μM, 1 μM, 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Induced caspase-3/7 activity in cultured human pulmonary smooth muscle cells. |
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| Animal Protocol |
Animal/Disease Models: Female C57BL/6 J mice (7-12 week-old) with hypoxic-induced pulmonary arterial hypertension[2]
Doses: 1 mg/kg Route of Administration: intraperitoneal (ip)injection; every second day; for 21 days Experimental Results: decreased right ventricular hypertrophy. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor Nrf-2. |
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| References |
[1]. Schnute ME, et al. Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem J. 2012 May 15;444(1):79-88.
[2]. MacRitchie N, et al. Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension. Cell Signal. 2016 Aug;28(8):946-55. [3]. Hamada M, et al. Induction of autophagy by sphingosine kinase 1 inhibitor PF-543 in head and neck squamous cell carcinoma cells. Cell Death Discov. 2017 Aug 14;3:17047. |
| Molecular Formula |
C27H32CLNO4S
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|---|---|
| Molecular Weight |
502.066
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| CAS # |
1706522-79-3
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| Related CAS # |
PF-543;1415562-82-1;PF-543 Citrate;1415562-83-2
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| SMILES |
Cl.S(C1C=CC=CC=1)(CC1C=C(C)C=C(C=1)OCC1C=CC(=CC=1)CN1CCC[C@@H]1CO)(=O)=O
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| Synonyms |
PF543 PF-543 HCl PF 543 PF543
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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