ABC294640

ABC294640 is an inhibitor of sphingolipid metabolism.^1,2,3 ABC294640 was originally identified as a selective inhibitor of sphingosine kinase 2 (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, when used at a concentration of 50 µM.^1,3 It reduces 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.² ABC294640 also inhibits sphingolipid delta(4)-desaturase (DES1; IC₅₀ = 10.2 µM in Jurkat cells). It is inactive against a panel of 20 lipid-regulated kinases at 50 μM.¹ It decreases sphingosine-1-phosphate (S1P) production in MDA-MB-231 breast cancer cells but increases S1P and dihydrosphingosine-1-phosphate (dhS1P) levels in Chang, HepG2, and HK-2 cells, as well as human umbilical vein endothelial cells (HUVECs).^1,3 ABC294640 inhibits the proliferation of several cancer cell lines, including HepG2, A-498, PANC-1, and HT-29 (IC₅₀s = 6, 12.2, 32.8, and 48.1 µM, respectively).¹ It reduces actin filament polymerization in, and 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).⁴

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1. French, K.J., Zhuang, Y., Maines, L.W., et al. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J. Pharmacol. Exp. Ther. 333(1), 129-139 (2010).

2. McNaughton, M., Pitman, M., Pitson, S.M., et al. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells. Oncotarget 7(13), 16663-16675 (2016).

3. Prell, A., Wigger, D., Huwiler, A., et al. The sphingosine kinase 2 inhibitors ABC294640 and K145 elevate (dihydro)sphingosine 1-phosphate levels in various cells. J. Lipid Res. 65(10), 100631 (2024).

4. Maines, L.W., Fitzpatrick, L.R., Green, C.L., et al. Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease. Inflammopharmacology 18(2), 73-85 (2010).