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
  • 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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