Development of a sphingosine kinase 1 specific small-molecule inhibitor

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7498-502. doi: 10.1016/j.bmcl.2010.10.005. Epub 2010 Nov 1.

Abstract

The sphingolipid metabolic pathway represents a potential source of new therapeutic targets for numerous hyperproliferative/inflammatory diseases. Targets such as the sphingosine kinases (SphKs) have been extensively studied and numerous strategies have been employed to develop inhibitors against these enzymes. Herein, we report on the optimization of our novel small-molecule inhibitor SKI-I (N'-[(2-hydroxy-1-naphthyl)methylene]-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide) and the identification of a SphK1-specific analog, SKI-178, that is active in vitro and in vivo. This SphK1 specific small-molecule, non-lipid like, inhibitor will be of use to elucidate the roles of SphK1 and SphK2 in the development/progression of hyperproliferative and/or inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / toxicity
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry*
  • Hydrazines / toxicity
  • Kinetics
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / toxicity
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hydrazines
  • N'-((1E)-1-(3,4-dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide
  • N'-((2-hydroxy-1-naphthyl)methylene)-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide
  • Pyrazoles
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase