A small molecule that inhibits OGT activity in cells.

Therapeutic Approaches

Abstract

O-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of O-linked N-acetylglucosamine (O-GlcNAc) residues to nuclear and cytoplasmic proteins. Its targets include kinases, phosphatases, transcription factors, histones, and many other intracellular proteins. The biology of O-GlcNAc modification is still not well understood, and cell-permeable inhibitors of OGT are needed both as research tools and for validating OGT as a therapeutic target. Here, we report a small molecule OGT inhibitor, OSMI-1, developed from a high-throughput screening hit. It is cell-permeable and inhibits protein O-GlcNAcylation in several mammalian cell lines without qualitatively altering cell surface N- or O-linked glycans. The development of this molecule validates high-throughput screening approaches for the discovery of glycosyltransferase inhibitors, and further optimization of this scaffold may lead to yet more potent OGT inhibitors useful for studying OGT in animal models.

Authors

Ortiz-Meoz, Rodrigo F; Jiang, Jiaoyang; Lazarus, Michael B; Orman, Marina; Janetzko, John; Fan, Chenguang; Duveau, Damien; Tan, Zhi-Wei; Thomas, Craig; Walker, Suzanne;

Keywords

  • Animals
  • CHO Cells
  • Cell Membrane Permeability
  • Cricetulus
  • Enzyme Inhibitors/ chemical synthesis
  • Enzyme Inhibitors/ pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Lectins/ chemistry
  • Lectins/ metabolism
  • N-Acetylglucosaminyltransferases/ antagonists & inhibitors
  • N-Acetylglucosaminyltransferases/ chemistry
  • N-Acetylglucosaminyltransferases/ metabolism
  • Small Molecule Libraries/ chemical synthesis
  • Small Molecule Libraries/ pharmacology
  • Uridine Diphosphate/ chemistry
  • Uridine Diphosphate/ metabolism
  • Uridine Diphosphate N-Acetylglucosamine/ chemistry
  • Uridine Diphosphate N-Acetylglucosamine/ metabolism

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