Biological Characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a Selective Sphingosine Kinase-2 Inhibitor and Anticancer Agent

Abstract

In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors.

A real-time high-throughput fluorescence assay for sphingosine kinases

“…4C ), which is in excellent agreement with previous reports ( 20 ). We also examined the effect of the SphK2-specifi c inhibitor K145 ( 21 ). As can be seen in Fig.…”

“…As can be seen in Fig. 4D , K145 suppressed SphK2 activity with an IC 50 of 33.7 µM, which is slightly higher than the K i value determined with the conventional radioactive assay ( 21 ). Taken together, these results suggest that our new fl uorescence method is suitable for rapid screening of SphK1 and SphK2 inhibitors.…”

Sphingosine Kinase 2 Promotes Acute Lymphoblastic Leukemia by Enhancing MYC Expression

“…Recently, sphingolipid metabolism was shown to be required for activation of BAK and BAX and apoptosis induction (38). However, recent studies have demonstrated a role for SK2 in tumor promotion (11,35) and demonstrated that inhibition of SK2 can inhibit the in vitro and in vivo growth of the myeloid leukemia cell line, U937 (39). We examined the effects of Sphk2 deletion in the development of BCR/ABL-driven ALL, and SK2 inhibition in ALL cells in vitro and in vivo.…”

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

“…by guest, on www.jlr.org Downloaded from as xenograft growth of tumor cells in mice (34,35). Studies with FTY720, a S1P mimetic prodrug, have also served to demonstrate the role of S1P.…”