Inhibitors of specific ceramide synthases

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• 作者：Susanne Schiffmann^a ; Daniela Hartmann^a ; Sina Fuchs^a ; Kerstin Birod^a ; Nerea Ferreirò ; s^a ; Yannick Schreiber^a ; Aleksandra Zivkovic^b ; Gerd Geisslinger^a ; Sabine Grö ; sch^a ; Holger Stark^b ; ^{h.stark@zafes.de}
• 关键词：Ceramide synthase ; Ceramide ; Inhibitor ; Ceramide synthase activity assay
• 刊名：Biochimie
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：94
• 期：2
• 页码：558-565
• 全文大小：1070 K

文摘

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.