PF-543 Citrate (Sphingosine Kinase 1 Inhibitor II Citrate) is a potent, selective, reversible and sphingosine-competitive SPHK1 inhibitor with an IC₅₀ of 2 nM and a K_i of 3.6 nM. PF-543 Citrate is >100-fold selectivity for SPHK1 over SPHK2. PF-543 Citrate is an effective potent inhibitor of sphingosine 1-phosphate (S1P) formation in whole blood with an IC₅₀ of 26.7 nM. PF-543 Citrate induces apoptosis, necrosis, and autophagy^[1][2][3]. IC50 & Target: IC50: 2 nM (SPHK1); 26.7 nM (Sphingosine 1-phosphate (S1P))^[1]
Ki: 3.6 nM (SPHK1)^[1] In Vitro: PF-543 (10-1000 nM; 24 hours; PASM cells) treatment abolishes SK1 expression at nM concentrations^[2].
PF-543 (0.1-10 μM; 24 hours; PASM cells) treatment induces caspase-3/7 activity^[2].
PF-543 inhibits C₁₇-S1P formation in 1483 cells with an IC₅₀ of 1.0 nM^[1].
SphK1 inhibition by PF-543 causes a dose-dependent depletion of the intracellular level of S1P with EC₅₀ concentration of 8.4 nM and a concomitant elevation of the intracellular level of sphingosine in 1483 cells. The level of endogenous S1P in 1483 cells after a 1 h treatment with 200 nM PF-543 is decreased 10-fold, producing a proportional increase in the level of sphingosine^[1]. 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 T_1/2 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].