4.8 Article

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

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 140, Issue 42, Pages 13542-13545

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b07328

Keywords

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Funding

  1. NIH Kirschstein NRSA [GM117704]
  2. Singapore A*STAR NSS fellowship
  3. NSERC of Canada PGS-M and D3 fellowships
  4. [GM094263]
  5. [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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