Elevation of cellular O-GlcNAcylation level by a potent and selective O-GlcNAcase inhibitor based on tetrahydroimidazopyridine scaffold

Bioorg Med Chem Lett. 2012 Nov 15;22(22):6854-7. doi: 10.1016/j.bmcl.2012.09.042. Epub 2012 Sep 23.

Abstract

Protein O-GlcNAc glycosylation is a ubiquitous post-translational modification in metazoans. O-GlcNAcase (OGA), which is responsible for removing O-GlcNAc from serine or threonine residues, plays a key role in O-GlcNAc metabolism. Potent and selective O-GlcNAcase (OGA) inhibitors are useful tools for investigating the role of this modification in a broad range of cellular processes, and may also serve as drug candidates for treatment of neurodegenerative diseases. Biological screening of the gluco-configured tetrahydroimidazopyridine derivatives identified a compound as a potent and competitive inhibitor of human O-GlcNAcase (OGA) with a K(i) of 5.9 μM, and it also displayed 28-fold selectivity for human OGA over human lysosomal β-hexosaminidase A (Hex A, K(i)=163 μM). In addition, cell-based assay revealed that this compound was cell-permeant and effectively induced cellular hyper-O-GlcNAcylation at 10 μM concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Glycosylation / drug effects
  • Hexosaminidase A / antagonists & inhibitors
  • Hexosaminidase A / metabolism
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology
  • Kinetics
  • Lysosomes / enzymology
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • beta-N-Acetylhexosaminidases / antagonists & inhibitors*
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • hexosaminidase C
  • Hexosaminidase A
  • beta-N-Acetylhexosaminidases
  • pyridine