2. Academic Validation
  3. Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors

Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors

  • J Am Chem Soc. 2018 Oct 24;140(42):13542-13545. doi: 10.1021/jacs.8b07328.
Sara E S Martin 1,  Zhi-Wei Tan 1,  Harri M Itkonen 1,  Damien Y Duveau 2,  Joao A Paulo 3,  John Janetzko 1 4,  Paul L Boutz 5,  Lisa Törk 4,  Frederick A Moss 1,  Craig J Thomas 2,  Steven P Gygi 3,  Michael B Lazarus 6,  Suzanne Walker 1
Affiliations

Affiliations

  • 1 Department of Microbiology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 2 Division of Preclinical Innovation, National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , Maryland 20892 , United States.
  • 3 Department of Cell Biology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 4 Department of Chemistry and Chemical Biology , Harvard University , Cambridge , Massachusetts 02138 , United States.
  • 5 The David H. Koch Institute for Integrative Cancer Research , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.
  • 6 Department of Pharmacological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
PMID: 30285435 DOI: 10.1021/jacs.8b07328
Abstract

Reversible glycosylation of nuclear and cytoplasmic proteins is an important regulatory mechanism across metazoans. One Enzyme, O-linked N-acetylglucosamine transferase (OGT), is responsible for all nucleocytoplasmic glycosylation and there is a well-known need for potent, cell-permeable inhibitors to interrogate OGT function. Here we report the structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity. In addition to disclosing useful OGT inhibitors, the structures we report provide insight into how to inhibit glycosyltransferases, a family of enzymes that has been notoriously refractory to inhibitor development.

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