PF-543 is a novel and cell-permeant inhibitor of Sphingosine kinase (SphK1) with IC50 value of 3.6 nM [1],
SphK1 is a kinase that phosphorylates sphingosine to sphingosine-1-phosphate (SIP). SphK1 is normally a cytosolic protein but can be recruited to the membrane to conduct its activity. It is the major source of production of S1P which promotes cell growth, survival and migration, and also regulate lymphocyte trafficking.
Biochemical study has identified that SphK1 was a sphingosine-competitive inhibitor but not ATP-competitive [1]. In 1483 head and neck carcinoma cell cultures expressing high levels of SphK1 and with an unusually high rate of S1P production, pretreatment of PF-543 for 1 hr decreased the level of endogenous S1P by 10-fold with a proportional increase in the level of sphingosine. It indicated a significant inhibition of SphK1 BY pf-543. However, speci?c inhibition of SphK1 had no effect on the proliferation and survival of 1483 cell cultures, despite a dramatic change in the cellular S1P/sphingosine rate [1].
The inhibitory activity of PF-543 was also examined ex vivo in human whole blood. Human whole blood with high SphK1 activity was prepared, which was able to quickly convert C17-sphingosine to C17-S1P. PF-543 treatment showed that PF-543 was a potent inhibitor of SphK1, capable of blocking >90% C17-S1P formation [1].
Reference:
[1] Schnute M E et al.?, Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem J. 2012, 444(1): 79-88.
