Chemicals & Small Molecules

ABC294640 (Opaganib) is an orally bioavailable selective inhibitor of sphingosine kinase 2 (SPHK2 or SK2). Sphingosine kinases phosphorylate sphingosine producing the bioactive lipid sphingosine 1-phosphate which has roles in cell proliferation and cell motility. Sphingosine kinases are up-regulated in numerous forms of cancer and ABC294640 alone or in combination has been shown to suppress growth in kidney breast liver colon and lung cancer cell lines.References Powered by Bioz See more details on Bioz

PF-543 is a potent inhibitor of sphingosine kinase 1 (SK1; IC50 = 2-3.6 nM) that less effectively inhibits SK2 (IC50 = 356 nM).(1) It does not significantly block the activity of other protein and lipid kinases or bind sphingosine-1-phosphate receptors when tested at a concentration of 10 μM.1 PF-543 prevents the phosphorylation of sphingosine in cancer cells and in whole blood (EC50 = 8.4 and 27 nM respectively).1 Through its effects on SK1 PF-543 prevents sickling hemolysis and inflammation in sickling cell disease transgenic mice.(2) Unlike inhibitors that are selective for SK2 PF-543 does not impair DNA synthesis in human pulmonary arterial smooth muscle cells.(3)

SKI-II is a commonly used inhibitor of both sphingosine kinase I (SPHK1) and 2 (SPHK2). Recently it has been shown to inhibit dihydroceramide desaturase (Des1) which Aurelio et al. suggest is actually responsible for its anti-proliferative activity not SPHK inhibition. Compound 34 is an analog of SKI-II and is a selective Des1 inhibitor which shows no activity against either SPHK1 or SPHK2. 34 inhibits PC3 cell growth (GIC50 = 0.34 μM) but some of this may be due to inhibition of another targetReferences Powered by Bioz See more details on BiozL. Aurelio C.V. Scullino et al.. “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)” J. Med. Chem. 59 965-984 DOI: 10.1021/acs.jmedchem.5b01439.

SKI-178 is a selective inhibitor of sphingosine kinase 1 which is active in vitro and in vivo. SKI-178 is a competitive inhibitor of sphingosine binding to SPHK1 (Ki = 1.3 uM) and shows no inhibition of SPHK2 up to 25 uM. SKI-178 is cytotoxic to numerous cancer cell lines (MCF-7 A549 Panc-1 etc) at low to sub-micromolar concentrations.

THI is a trace component present in the industrially produced food colorant caramel color III. It acts as an immunosuppressant by inhibiting the enzyme sphingosine 1-phosphate lyase (S1PL) which fragments S1P to hexadecenal and phosphoethanolamine. Administration of THI in drinking water to mice (50 μg/mL) resulted in decreased S1PL activity increased S1P levels in lymphoid tissues and reduced egress of CD4+ and CD8+ T cells (lymphopenia).

1-Methylhistamine (N-Tau-MethylHistamine:2HCl) is a histamine metabolite that has been used as a biomarker of Alzheimer's disease and other neurological disorders. It is a formed by histamine 1-methyltransferase in the histidine metabolism pathway.

NVP-231 is a potent specific and reversible Ceramide kinase (CerK) inhibitor (IC50= 12 nM in vitro) which competitively inhibits binding of ceramide. CerK is a key enzyme for controlling ceramide levels.ReferencesGraf C. et al. Targeting Ceramide Metabolism with a Potent and Specific Ceramide Kinase Inhibitor; Molecular Pharmacology 2008 74(4): 925-932

Acid ceramidase (aCDase) is a lysosomal amidase which hydrolyzes the acyl chain from ceramides forming sphingosine which is subsequently phosphorylated to the bioactive lipid sphingosine 1-phosphate. aCDase is upregulated in many cancer types such as melanoma prostate head neck and colon cancers. ARN14988 is a potent inhibitor of aCDase in vitro (IC50 = 12 nM) and in A375 melanoma cells (IC50 = 1.5uM). ARN14988 is weakly cytotoxic by itself but shows a synergystic effect with some common anti-cancer drugs (5-Fluorouracil vemurafinib and taxol) in proliferative G361 cells.

Ceramides are bioactive sphingolipids which induce apoptosis in cells. Ceramidases which hydrolyze the fatty acid chain keep ceramide levels in check and have been proposed as a target for small-molecule inhibitors for anti-cancer therapy. B13 (or D-NMAPPD) is a potent ceramidase inhibitor which causes aopotosis in a number of cell lines including colorectal HL60 melanoma and keratinocyes.References1) A. Bielawska C.M. Linardic Y. Hannun "Ceramide-mediated biology. Determination of structural and stereospecific requirements through the use of N-acyl-phenylaminoalcohol analogs" J. Biol. Chem. 1992 267 18493-7. 2) M. Raisova G. Goltz et al. "Bcl-2 overexpression prevents apoptosis induced by ceramidase inhibitors in malignant melanoma and HaCaT keratinocytes" FEBS Letters 2002 516 47-52. 3) Bhabak Krishna P.; Kleuser Burkhard "Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues" Bioorganic & Medicinal Chemistry 2013 21 874-882.