ABC294640 is an inhibitor of sphingosine kinase 2 (SPHK2; Ki = 9.8 μM). It inhibits SPHK2 (IC50 = 60 μM) without affecting SPHK1 activity up to 100 μM but does reduce SPHK1 isoform a (SPHK1a) protein levels in androgen-independent LNCaP (LNCaP-AI) cells via an SPHK1-indirect, proteasomal-dependent mechanism when used at concentrations ranging from 5 to 25 μM. ABC294640 is inactive against a panel of 20 lipid-regulated kinases at 50 μM. It decreases sphingosine-1-phosphate (S1P) production in MDA-MB-231 cells in a concentration-dependent manner. ABC294640 inhibits proliferation of a variety of cancer cells, including HepG2 liver, A-498 kidney, PANC-1 pancreas, and HT-29 colon cells (IC50s = 6, 12.2, 32.8, and 48.1 μM, respectively). It reduces actin filament polymerization in, and cell migration of, A-498 cells in a scratch assay. Oral administration of ABC294640 (35 and 100 mg/kg every other day) reduces tumor growth in a mouse syngeneic model of mammary adenocarcinoma. It also reduces colonic inflammation in mouse and rat models of Crohn’s disease induced by trinitrobenzene sulfonic acid (TNBS).
