title: Inhibitors of specific ceramide synthases.
abstract: Ceramide synthases (CerSs) are key enzymes in the biosynthesis of ceramides and display a group of at least six different isoenzymes (CerS1-6). Ceramides itself are bioactive molecules. Ceramides with different N-acyl side chains (C(14:0)-Cer - C(26:0)-Cer) possess distinct roles in cell signaling. Therefore, the selective inhibition of specific CerSs which are responsible for the formation of a specific ceramide holds promise for a number of new clinical treatment strategies, e.g., cancer. Here, we identified four of hitherto unknown functional inhibitors of CerSs derived from the FTY720 (Fingolimod) lead structure and showed their inhibitory effectiveness by two in vitro CerS activity assays. Additionally, we tested the substances in two cell lines (HCT-116 and HeLa) with different ceramide patterns. In summary, the in vitro activity assays revealed out that ST1058 and ST1074 preferentially inhibit CerS2 and CerS4, while ST1072 inhibits most potently CerS4 and CerS6. Importantly, ST1060 inhibits predominately CerS2. First structure-activity relationships and the potential biological impact of these compounds are discussed.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
authors.forename: Daniela
authors.initials: D
authors.lastname: Hartmann
authors.forename: Sina
authors.initials: S
authors.lastname: Fuchs
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiròs
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schreiber
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zivkovic
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011409:Propylene Glycols / Q000138:chemical synthesis / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D002518:Ceramides; D007527:Isoenzymes; D011409:Propylene Glycols; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine