PF-543 is a potent inhibitor of sphingosine kinase 1 (SK1; IC50 = 2-3.6 nM) that less effectively inhibits SK2 (IC50 = 356 nM).(1) 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.1 PF-543 prevents the phosphorylation of sphingosine in cancer cells and in whole blood (EC50 = 8.4 and 27 nM, respectively).1 Through its effects on SK1, PF-543 prevents sickling, hemolysis, and inflammation in sickling cell disease transgenic mice.(2) Unlike inhibitors that are selective for SK2, PF-543 does not impair DNA synthesis in human pulmonary arterial smooth muscle cells.(3)
1) M. E. Schnute, M. D. McReynolds, T. Kasten, et al. “Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1” Biochemistry Journal 2012, 444, 79-88.
2) Y. Zhang, V. Berka, A. Song, et al. “Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression.” J. Clin. Invest. 2014, 124, 2750-2761.
3) H. S. Byun, S. Pyne, N. Macritchie, et al. “Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells.” Med. Chem. Comm. 2013, 4, 1-15.