Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 140, Issue 42, Pages 13542-13545Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b07328
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Funding
- NIH Kirschstein NRSA [GM117704]
- Singapore A*STAR NSS fellowship
- NSERC of Canada PGS-M and D3 fellowships
- [GM094263]
- [GM124838]
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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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