K145

K145 is a selective inhibitor of Sphingosine Kinase-2 (SphK2) with IC50 value of 4.3μM [1].

K145 is an analogue of sphingosine. It competes with the substrate of SphK2 and shows Ki value of 6.4μM in the in vitro assay. K145 is selective against SphK2 over SphK1 and CERK. In U937 cells, K145 decreases total cellular S1P and inhibits the phosphorylation of FTY720 (Both S1P and FTY720 are substrates of SphK2). Meanwhile, K145 suppresses cell growth and induces late apoptosis significantly. It is also found to inhibit the phosphorylation of ERK and Akt in this cell line [1].

In the U937 xenograft model in mice, K145 inhibits tumor growth with a TGI value of 44.2% and has less toxicity than tamibarotene. In BALB/c mice bearing the JC xenograft, K145 also shows potent inhibitory effects on tumor growth. Moreover, in BALB/c-nu mice bearing U937 xenograft, oral administration of K145 exerts better antitumor activity than tamibarotene [1].

References:
[1] Liu K, Guo T L, Hait N C, et al. 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. PloS one, 2013, 8(2): e56471.

Interactions of acetylcholine binding site residues contributing to nicotinic acetylcholine receptor gating: role of residues Y93, Y190, K145 and D200.[Pubmed:23831994]

J Mol Graph Model. 2013 Jul;44:145-54.

The nicotinic acetylcholine receptor exhibits multiple conformational states, resting (channel closed), active (channel open) and desensitized (channel closed). The resting state may be distinguished from the active and desensitized states by the orientation of loop C in the extracellular ligand binding domain (LBD). Homology modeling was used to generate structures of the Torpedo californica alpha2betadeltagamma nAChR that initially represent the resting state (loop C open) and the desensitized state (loop C closed). Molecular dynamics (MD) simulations were performed on the extracellular LBD on each nAChR conformational state, with and without the agonist anabaseine present in each binding site (the alphagamma and the alphadelta sites). Three MD simulations of 10ns each were performed for each of the four conditions. Comparison of dynamics revealed that in the presence of agonist, loop C was drawn inward and attains a more stable conformation. Examination of side-chain interactions revealed that residue alphaY190 exhibited hydrogen-bonding interactions either with residue alphaY93 in the ligand binding site or with residue alphaK145 proximal to the binding site. alphaK145 also exhibited side chain (salt bridge) interactions with alphaD200 and main chain interactions with alphaY93. Residues alphaW149, alphaY198, gammaY116/deltaT119, gammaL118/deltaL121 and gammaL108/deltaL111 appear to play the role of stabilizing ligand in the binding site. In MD simulations for the desensitized state, the effect of ligand upon the interactions among alphaK145, alphaY190, and alphaY93 as well as ligand-hydrogen-bonding to alphaW149 were more pronounced at the alphagamma interface than at the alphadelta interface. Differences in affinity for the desensitized state were determined experimentally to be 10-fold. The changes in side chain interactions observed for the two conformations and induced by ligand support a model wherein hydrogen bond interactions between alphaD200 and alphaY93 are broken and rearrange to form a salt-bridge between alphaK145 and alphaD200 and hydrogen bond interactions between alphaY93 and alphaY190 and between alphaK145 and alphaY190.

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.[Pubmed:23437140]

PLoS One. 2013;8(2):e56471.

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.

K145 is a selective, substrate-competitive and orally active SphK2 inhibitor with an IC50 of 4.3 µM and a Ki of 6.4 µM. K145 is inactive against SphK1 and other protein kinases. K145 induces cell apoptosis and has potently antitumor activity.

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