Abstract
O-GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use. Here, we describe our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an in silico fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC50 values in the micromolar range.
Highlights
Hao Zhang,a Tihomir Tomašič, b Jie Shi,a Matjaž Weiss,b Rob Ruijtenbeek,ac Marko Anderluh b and Roland J
The existing O-GlcNAc transferase (OGT) inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use
We describe our progress on OGT inhibition based on substrate peptides identified by array screening
Summary
Hao Zhang,a Tihomir Tomašič, b Jie Shi,a Matjaž Weiss,b Rob Ruijtenbeek,ac Marko Anderluh b and Roland J. Through catalyzing the attachment of N-acetylglucosamine to specific serines and threonines of proteins, OGT is associated with numerous biological processes such as transcription, the cell cycle progression, the stress response and nutrient sensing.[1,2,3,4,5] Prior studies have noted the potential of OGT as a therapeutic target because it is one of only two enzymes modulating O-GlcNAcylation and because its expression is correlated with the metabolic status of a cell directly.[6,7,8,9] In metabolic diseases like cancer and diabetes, increase of various metabolic products like glucose into the cell alters the production of UDP-GlcNAc through the hexosamine biosynthetic pathway.
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