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).
Opaganib is used in treating iatrogenic autoimmune colitis.
ChEBI: 3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)-1-adamantanecarboxamide is an organochlorine compound.
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].
[1] french k j, zhuang y, maines l w, et al. pharmacology and antitumor activity of abc294640, a selective inhibitor of sphingosine kinase-2. journal of pharmacology and experimental therapeutics, 2010, 333(1): 129-139.
[2] antoon j w, white m d, meacham w d, et al. antiestrogenic effects of the novel sphingosine kinase-2 inhibitor abc294640. endocrinology, 2010, 151(11): 5124-5135.
