- Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.
Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.
Journal of the American Chemical Society (2018-10-05)
Sara E S Martin, Zhi-Wei Tan, Harri M Itkonen, Damien Y Duveau, Joao A Paulo, John Janetzko, Paul L Boutz, Lisa Törk, Frederick A Moss, Craig J Thomas, Steven P Gygi, Michael B Lazarus, Suzanne Walker
PMID30285435
초록
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.
MATERIALS