PF-543 Citrate (Sphingosine Kinase 1 Inhibitor II Citrate) is a novel cell-permeant inhibitor of SPHK1 with a Ki of 4.3 nM and more than 100-fold selectivity for SPHK1 over SPHK2.
PF-543 Citrate (Sphingosine Kinase 1 Inhibitor II Citrate) is a novel selective sphingosine-competitive inhibitor of SphK1 that is over 1000-fold more potent in suppressing cellular S1P formation than DMS and SKI-2, commonly used pharmacological tools for SphK. PF-543 inhibits SphK1 with a Ki of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreases the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine[1]. PF-543 inhibits SphK1 in the in vitro enzyme assay with an IC50 value of 2.0±0.6 nM and is able to inhibit the enzyme >95% at a concentration of 20 nM[1]. PF-543 bounds in a bent conformation analogous to that expected of a bound sphingosine substrate but with a rotated head group[2].
Administration of the potent sphingosine kinase 1 inhibitor, PF-543 Citrate (Sphingosine Kinase 1 Inhibitor II Citrate) in a mouse hypoxic model of pulmonary hypertension has no effect on vascular remodelling but reduces right ventricular hypertrophy. Administration of 10 mg/kg PF-543 for 24 h to mice induces a decrease in SK1 expression in pulmonary vessels[3].
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]. Wang J, et al. Crystal Structure of Sphingosine Kinase 1 with PF-543. ACS Med Chem Lett. 2014 Oct 27;5(12):1329-33.
[3]. 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.