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

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.