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J Am Chem Soc. 2018 Oct 24;140(42):13542-13545. doi: 10.1021/jacs.8b07328. Epub 2018 Oct 4.

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

Author information

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.

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.

PMID:
30285435
PMCID:
PMC6261342
[Available on 2019-10-24]
DOI:
10.1021/jacs.8b07328
[Indexed for MEDLINE]

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