PF-543 is a potent inhibitor of sphingosine kinase 1 (SK1; IC50 = 2-3.6 nM) that less effectively inhibits SK2 (IC50 = 356 nM). It does not significantly block the activity of other protein and lipid kinases, or bind sphingosine-1-phosphate receptors, when tested at a concentration of 10 μM. PF-543 prevents the phosphorylation of sphingosine in cancer cells and in whole blood (EC50s = 8.4 and 27 nM, respectively). Through its effects on SK1, PF-543 prevents sickling, hemolysis, and inflammation in sickling cell disease transgenic mice. Unlike inhibitors that are selective for SK2, PF-543 does not impair DNA synthesis in human pulmonary arterial smooth muscle cells.
