ABC294640

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An inhibitor of sphingolipid metabolism; originally identified as a selective inhibitor of SPHK2 (IC50 = ~60 µM for the recombinant human enzyme) without activity against SPHK1 up to 100 µM but was later shown to inhibit recombinant human SPHK1 and SPHK2 by 32-34% and 21%, respectively, at 50 µM; reduces SPHK1a protein levels in LNCaP-AI cells via an SPHK1-indirect, proteasomal-dependent mechanism from 5-25 µM; inhibits DES1 (IC50 = 10.2 µM in Jurkat cells); inactive against a panel of 20 lipid-regulated kinases at 50 µM; decreases S1P production in MDA-MB-231 cells but increases S1P and dhS1P levels in Chang, HepG2, and HK-2 cells and HUVECs; inhibits the proliferation of several cancer cell lines (IC50s = 6-48.1 µM); reduces actin filament polymerization in, and migration of, A-498 cells in a scratch assay; reduces tumor growth in a mouse syngeneic model of mammary adenocarcinoma; reduces TNBS-induced colonic inflammation in mouse and rat models of Crohn’s disease