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

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...

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Published inJournal of the American Chemical Society Vol. 140; no. 42; pp. 13542 - 13545
Main Authors Martin, Sara E. S, Tan, Zhi-Wei, Itkonen, Harri M, Duveau, Damien Y, Paulo, Joao A, Janetzko, John, Boutz, Paul L, Törk, Lisa, Moss, Frederick A, Thomas, Craig J, Gygi, Steven P, Lazarus, Michael B, Walker, Suzanne
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 24.10.2018
American Chemical Society (ACS)
Subjects
Animalia
enzyme inhibition
enzyme inhibitors
glycosylation
glycosyltransferases
N-acetylglucosamine
proteins
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Summary: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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National Institutes of Health (NIH)
Present Addresses
Chemistry Department, The College of Wooster, 931 College Mall, Wooster, OH 44691
Department of Molecular and Cellular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305, USA
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.8b07328