title: Discovery and evaluation of inhibitors of human ceramidase.
abstract: The ceramide/sphingosine-1-phosphate (S1P) rheostat has been hypothesized to play a critical role in regulating tumor cell fate, with elevated levels of ceramide inducing death and elevated levels of S1P leading to survival and proliferation. Ceramidases are key enzymes that control this rheostat by hydrolyzing ceramide to produce sphingosine and may also confer resistance to drugs and radiation. Therefore, ceramidase inhibitors have excellent potential for development as new anticancer drugs. In this study, we identify a novel ceramidase inhibitor (Ceranib-1) by screening a small molecule library and describe the synthesis of a more potent analogue (Ceranib-2). In a cell-based assay, both compounds were found to inhibit cellular ceramidase activity toward an exogenous ceramide analogue, induce the accumulation of multiple ceramide species, decrease levels of sphingosine and S1P, inhibit the proliferation of cells alone and in combination with paclitaxel, and induce cell-cycle arrest and cell death. In vivo, Ceranib-2 was found to delay tumor growth in a syngeneic tumor model without hematologic suppression or overt signs of toxicity. These data support the selection of ceramidases as suitable targets for anticancer drug development and provide the first nonlipid inhibitors of human ceramidase activity.
authors: Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors: Jeremiah M
authors: JM
authors: Draper
authors: Zuping
authors: Z
authors: Xia
authors: Ryan A
authors: RA
authors: Smith
authors: Yan
authors: Y
authors: Zhuang
authors: Wenxue
authors: W
authors: Wang
authors: Charles D
authors: CD
authors: Smith
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055572:Ceramidases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries
chemical_list: C000602531:3-(3-(4-methoxyphenyl)acryloyl)-4-phenyl-1H-quinolin-2-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D054852:Small Molecule Libraries; D055572:Ceramidases