title: Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels.
abstract: Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States.
authors.forename: Lina
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States.
authors.forename: Adam D
authors.identifier: 0000-0003-0754-1638
authors.initials: AD
authors.lastname: Linstedt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006031:Glycosylation; D051379:Mice; D017350:N-Acetylgalactosaminyltransferases / Q000037:antagonists & inhibitors*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse
keywords: FGF23; O-glycosylation; biosensor; cancer biology; cell biology; drug-like inhibitor; human; metastasis; mouse