Opaganib

Opaganib (ABC294640) is a selective, competitive sphingosine kinase 2 (SK2) inhibitor with K_i of 9.8 μM. IC50 & Target:Ki: 9.8 μM (SK2)^[1] In Vitro: Using recombinant human SK1 and SK2, Opaganib demonstrates dose-dependent inhibition of SK2 with an IC₅₀ of approximately 60 μM without affecting the activity of SK1 at concentrations up to at least 100 μM. In contrast, N,N-dimethylsphingosine (DMS) inhibits both SK1 and SK2 with IC₅₀ values of approximately 60 and 20 μM, respectively. Kinetic analyses of varying concentrations of Opaganib (ABC294640) in the presence of 2.5 to 25 μM sphingosine indicated a K_i of 9.8±1.4 μM for the inhibition of SK2. Opaganib (ABC294640) decreases [³H]S1P formation in a dose-dependent fashion with an IC₅₀ value of 26 μM^[1]. IC₅₀ values for Opaganib (ABC294640) are approximately 50 and 60 μM for A-498 and Bxpc-3 cells, respectively; whereas the IC₅₀ values for Opaganib (ABC294640) are approximately 20 and 40 μM for these cells^[2]. In Vivo: Opaganib induces a transient minor decrease in the hematocrit of rats. Hematology studies indicate decreases in red blood cell number and hematocrit of approximately 20% in animals given either 100 or 250 mg/kg/day; and a slight increase in neutrophils and decrease in basophils in the treated rats^[1]. Mice are gavaged with Opaganib (50 mg/kg), a selective inhibitor of sphingosine kinase-2 (SK2), 1 h before surgery and subjected to 1 h-warm ischemia to ~70% of the liver followed by reperfusion. Opaganib-treatment largely prevented the increase of sphingosine-1-phosphate (S1P) after ischemia-reperfusion (IR) in vivo^[2].