Abstract
Acid ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.
Highlights
The sphingolipids are ubiquitous lipid constituents of eukaryotic cell membranes.1 In addition to this essential structural function, sphingolipids are thought to play multiple signaling roles and to be involved in the pathogenesis of cancer,2 inflammation,3 and neuropathic pain.4 In particular, two key sphingolipids – ceramides and sphingosine 1-phosphate (S1P) – have been shown to regulate cell fate in opposite manner: ceramides by mediating cellular senescence5 and apoptosis,6 and S1P by promoting cell survival and proliferation
The lysosomal lipid amidase, acid ceramidase (AC, encoded by the ASAH-1 gene) is a key element of this rheostat. It catalyzes the hydrolysis of ceramides into fatty acid and sphingosine, which is converted into S1P by sphingosine kinase (SK) (Scheme 1)
Since 8 is a neutral molecule, the charge field usually included in atomic property field (APF) calculations was not taken into consideration
Summary
The sphingolipids are ubiquitous lipid constituents of eukaryotic cell membranes. In addition to this essential structural function, sphingolipids are thought to play multiple signaling roles and to be involved in the pathogenesis of cancer, inflammation, and neuropathic pain. In particular, two key sphingolipids – ceramides and sphingosine 1-phosphate (S1P) – have been shown to regulate cell fate in opposite manner: ceramides by mediating cellular senescence and apoptosis, and S1P by promoting cell survival and proliferation.. The ceramides are a highly heterogeneous family of Nacylated sphingosines with long-chain fatty acids.8 They hold a central role in sphingolipid metabolism and are the metabolic precursors of S1P; conversion of one into the other has been proposed to serve as a ‘rheostat’ in the regulation of cell fate.. The lysosomal lipid amidase, acid ceramidase (AC, encoded by the ASAH-1 gene) is a key element of this rheostat It catalyzes the hydrolysis of ceramides into fatty acid and sphingosine, which is converted into S1P by sphingosine kinase (SK) (Scheme 1).. Daniele Piomelli is the holder of Louise Turner Arnold Chair in Neurosciences and Professor of Anatomy and Neurobiology, Pharmacology and Biological Chemistry at the University of California, Irvine He is the founding director of the unit of drug discovery and development (D3) at the Italian Institute of Technology in Genoa, Italy
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