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O‐GlcNAcylation (O‐linked β‐N‐acetylglucosaminylation) is an important post‐translational and metabolic process in cells that is implicated in a wide range of physiological processes. O‐GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyses the transfer of O‐GlcNAc to nucleocytoplasmic proteins. Aberrant glycosylation by OGT has been linked to a variety of diseases including cancer, neurodegenerative disorders and diabetes. Previously, we and others demonstrated that O‐GlcNAcylation is notably elevated in hepatocellular carcinoma (HCC). The overexpression of O‐GlcNAcylation promotes cancer progression and metastasis. Here, we report the identification of HLY838, a novel diketopiperazine‐based OGT inhibitor with the ability to induce a global decrease in cellular O‐GlcNAc. HLY838 enhances the in vitro and in vivo anti‐HCC activity of CDK9 inhibitor by …