| Identification | Back Directory | [Name]
PF-543 | [CAS]
1706522-79-3 | [Synonyms]
PF 543 HCl
WNKWAZFYPZMDGJ-VQIWEWKSSA-N
PF-543 Hydrochloride
DISCONTINUED
(2R)-1-[[(4-[[3-Methyl-5-[(phenylsulfonyl)methyl]phenoxy]methyl]phenyl]methyl]-2-pyrrolidinemethanol hydrochloride | [Molecular Formula]
C27H32ClNO4S | [MOL File]
1706522-79-3.mol | [Molecular Weight]
502.065 |
| Hazard Information | Back Directory | [Uses]
(2R)-1-[[4-[[3-Methyl-5-[(phenylsulfonyl)methyl]phenoxy]methyl]phenyl]methyl]-2-pyrrolidinemethanol, is a novel Sphingonise Kinas 1 (SphK1, SK1) inhibitor. | [Enzyme inhibitor]
This potent SphK1 inhibitor (FWHCl-Salt = 502.07 g/mol; CAS 1706522-79- 3; Solubility: 10 mM in H2O, with gentle warming; 100 mM in DMSO), also named (2R)-1-[[(4-[[3-methyl-5-[(phenylsulfonyl)methyl]phenoxy] methyl]phenyl]methyl]-2-pyrrolidinemethanol hydrochloride, selectively targets sphingosine kinase 1 (IC50 = 2 nM; Ki = 3.6 nM). The latter phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), a lipid messenger with both intracellular functions (regulating cell proliferation and survival) and extracellular functions (as a ligand for EDG1, or sphingosine-1-phosphate receptor 1). PF-543 also exhibits >100-fold selectivity for Sphk1 over Sphk2 as well as >5000 fold selectivity over S1P1-5 receptors and 48 protein and lipid kinases. P 543 attenuates proliferation and induces necrosis in human colorectal cancer cells in vitro. It also suppresses human colorectal cancer cell line HCT-116 as a tumor xenograft growth in mice | [in vivo]
PF-543 (1 mg/kg; intraperitoneal injection; every second day; for 21 days; female C57BL/6 J mice) treatment has no effect on vascular remodelling but reduces right ventricular hypertrophy. The protection involves a reduction in the expression of p53 and an increase in the expression of anti-oxidant nuclear factor Nrf-2[2].
Mice are initially dosed (ip) with 10 mg/kg or 30 mg/kg of PF-543 for 24 h and the T1/2 is 1.2 h in blood samples. Administration of 10 mg/kg PF-543 for 24 h to mice induces a decrease in SK1 expression in pulmonary vessels[2]. | Animal Model: | Female C57BL/6 J mice (7-12 week-old) with hypoxic-induced pulmonary arterial hypertension[2] | | Dosage: | 1 mg/kg | | Administration: | Intraperitoneal injection; every second day; for 21 days | | Result: | Reduced 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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| [IC 50]
SphK1 | [storage]
Desiccate at RT |
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