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

• Published in: Journal of the American Chemical Society 2018-10, Vol.140 (42), p.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: Article
• Language: English
• Subjects: Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCT116 Cells; HEK293 Cells; Humans; Molecular Docking Simulation; N-Acetylglucosaminyltransferases - antagonists & inhibitors; N-Acetylglucosaminyltransferases - chemistry; N-Acetylglucosaminyltransferases - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.8b07328

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.