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ACS Chem Biol. 2015 Jun 19;10(6):1392-7. doi: 10.1021/acschembio.5b00004. Epub 2015 Mar 18.

A small molecule that inhibits OGT activity in cells.

Author information

1
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
2
‡National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States.

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.

PMID:
25751766
PMCID:
PMC4475500
DOI:
10.1021/acschembio.5b00004
[Indexed for MEDLINE]
Free PMC Article

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