SKI II

SKI II is an inhibitor of sphingosine kinase with IC50 value of 0.5μM[1].

SKI II is selective against SK and has no inhibition of human protein kinases ERK2, PKC-I and the lipid kinase PI3K. It is reported that SKI II is not a competitive inhibitor at the ATP-binding site of SK. SKI II also inhibits endogenous SK in intact MDA-MB-231 cells [1].

As a SK inhibitor, SKI II prevents SK from catalyzing the generation of sphingosine 1-phosphate (S1P). The blockage of S1P formation leads to inhibition of proliferation, as well as the induction of apoptosis in cancer cells. SKI II shows cytotoxicity in T-24 human bladder carcinoma cells, MCF-7 human breast adenocarcinoma cells and the subline of MCF-7 cells, MCF-7/VP, with IC50 values of 4.6μM, 1.2μM and 0.9μM, respectively [1].

References:
[1] French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, Yun JK, Smith CD. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003 Sep 15;63(18):5962-9.

From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure-Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II).[Pubmed:26780304]

J Med Chem. 2016 Feb 11;59(3):965-84.

The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results using this pharmacological agent are complicated by several factors: poor SK1/2 selectivity, additional activity as an inducer of SK1-degradation, and off-target effects, including its recently identified capacity to inhibit dihydroceramide desaturase-1 (Des1). In this study, we have delineated the structure-activity relationship (SAR) for these different targets and correlated them to that required for anticancer activity and determined that Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. In the course of these efforts, a series of novel SK1, SK2, and Des1 inhibitors have been generated, including compounds with significantly greater anticancer activity.

SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/beta-catenin signaling pathway.[Pubmed:26944438]

Life Sci. 2016 Apr 15;151:23-29.

AIM: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown. MAIN METHODS: The expressions of beta-catenin and related molecules of Wnt/beta-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of beta-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay. KEY FINDINGS: We found that SKI II decreased the expression of beta-catenin and the downstream molecules of beta-catenin signal pathway and promotes the beta-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered beta-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of beta-catenin and downstream molecules of beta-catenin signal pathway. SIGNIFICANCE: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated beta-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells.

SKI-II--a sphingosine kinase 1 inhibitor--exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (LDL-R-/-) mice on high cholesterol diet.[Pubmed:25801013]

Atherosclerosis. 2015 May;240(1):212-5.

BACKGROUND: Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice. METHODS AND RESULTS: LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-alpha and endothelial adhesion molecules (sICAM-1, sVCAM-1). CONCLUSION: Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia.

SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo.[Pubmed:25824043]

Biochem Biophys Res Commun. 2015 May 15;460(4):903-8.

Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, and concomitantly increased level of sphingosine-1-phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short-chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI-II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent.

Antitumor activity of sphingosine kinase inhibitors.[Pubmed:16632640]

J Pharmacol Exp Ther. 2006 Aug;318(2):596-603.

Sphingosine kinase (SK) is an oncogenic sphingolipid-metabolizing enzyme that catalyzes the formation of the mitogenic second messenger sphingosine-1-phosphate (S1P) at the expense of proapoptotic ceramide. Thus, SK is an attractive target for cancer therapy because blockage of S1P formation leads to inhibition of proliferation, as well as the induction of apoptosis in cancer cells. We have recently identified novel SK inhibitors with nanomolar to low micromolar potencies toward recombinant human SK. This study describes the continuing analysis of these inhibitors through in vitro and in vivo experiments. All three structurally diverse SK inhibitors tested showed antitumor activity in mice without exhibiting toxicity. Blood and tumor inhibitor concentrations exceeded in vitro potency levels. Cell signaling analyses in vitro revealed mixed inhibition of mitogen-activated protein kinase kinase and Akt phosphorylation by the SK inhibitors. Importantly, 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) is orally bioavailable, detected in the blood for at least 8 h, and showed a significant inhibition of tumor growth in mice. These compounds are the first examples of nonlipid selective inhibitors of SK with in vivo antitumor activity and provide leads for further development of inhibitors of this important molecular target.

SKI-II is an oral active and synthetic inhibitor of sphingosine kinase (SK) activity, with IC50 values of 78 μM and 45 μM for SK1 and for SK2, respectively. SKI II causes an irreversible inhibition of SK1 by inducing its lysosomal and/or proteasomal degradation.

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