O-Linked N-acetylglucosamine transferase (OGT) is responsible for the addition of β-N-acetylglucosamine (GlcNAc) to over 1,000 proteins in mammalian cells, and the addition of these O-GlcNAc groups to target proteins has been shown to affect localization, stability, enzymatic activity, and interactions with other biomolecules. Misregulation of OGT has been linked to cancer, diabetes, heart disease, and Alzheimer’s disease. However, studies of how OGT misregulation contributes to disease have been limited, in part because fast-acting chemical tools to manipulate OGT activity in cells have remained elusive. We report a series of probe compounds with nanomolar Kds, some of which are cell permeable. Crystal structures of several cocomplexes reveal that the quinolinone-6-sulfonamide portion of the molecules serves as a uridine mimic. Notably, we have identified an OGT mutation that reduces affinity for the inhibitor but not for the UDP-GlcNAc substrate, and cell lines containing this mutation may serve as useful controls for any off-target effects of the probe compounds. These inhibitors make possible future studies to elucidate the role of OGT in disease pathology and to test whether OGT inhibition may offer a therapeutic benefit.

New tools for the study of O-GlcNAc transferase in disease

254th National Meeting (2017)

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