MP-A08 is an ATP-competitive inhibitor of sphingosine kinases SPHK1 and SPHK2 (Kis = 27 and 6.9 μM, respectively).1 It is selective for SPHK1/2 over a panel of 140 human protein kinases at concentrations up to 25 μM. MP-A08 (15 μM) reduces generation of cellular sphingosine-1-phosphate without inducing degradation of SPHK1 in Jurkat cells. It induces a 3.7-, 3.5-, and 5.8-fold increase in C-18 ceramide , C-20 ceramide , and C20:1-ceramide levels, respectively, and dose-dependently activates the apoptosis-associated p38 and JNK pathways in vitro. MP-A08 reduces proliferation of a variety of human cancer cell lines (EC50s = 8-44.9 μM). MP-A08 also reduces tumor vasculature, as determined by CD31 staining, and volume as well as S1P protein levels in A549 human lung adenocarcinoma xenografts in mice.
1.Pitman, M.R., Powell, J.A., Coolen, C., et al.A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer propertiesOncotarget6(9)7065-7083(2015)