Discovery and evaluation of inhibitors of human ceramidase

Jeremiah M. Draper, Zuping Xia, Ryan A. Smith, Yan Zhuang, Wenxue Wang, Charles D. Smith

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2052-2061
Number of pages10
JournalMolecular cancer therapeutics
Volume10
Issue number11
DOIs
StatePublished - Nov 2011

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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