Sphingosine is an intermediate of sphingolipids that can be rapidly phosphorylated by sphingosine kinase (SK1 and SK2) to produce sphingosine 1-phosphate, which is a mitogenic compound. ABC294640 is a selective inhibitor of SK2 with a Ki value of 9.8 μM. ABC294640 dose-dependently inhibited recombinant human SK2 with an IC50 value of 60μM, while the activity of SK1 was not affected by ABC294640 at the concentration up to 100μM. In MDA-MB-231 cells, ABC294640 decreased [3H]S1P formation in a dose-dependent manner with an IC50 value of 26μM. ABC294640 also inhibited the proliferation of human tumor cell lines (1025LU, A-498, Caco-2, HT-29, DU145, SK-OV-3) with IC50 values ranging from 10.5-48.1μM[2]. In a mouse model of tri-nitrobenzene sulfonic acid (TNBS)-induced colitis, oral administration of ABC294640 (50mg/kg, twice daily) decreased TNBS-induced increase in mucosal myeloperoxidase activity by 60%. The histological analysis on colon sections revealed that the inflammation and damage caused by TNBS was reduced or negated by ABC294640 treatment[3].
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