11lj | pdb_000011lj
Human OGA IN COMPLEX WITH LIGAND 24
Structural highlights
FunctionOGA_HUMAN Isoform 1: Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:11148210). Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714).[1] [2] [3] [4] [5] Isoform 3: Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc as substrate but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro), but has about six times lower specific activity than isoform 1.[6] Publication Abstract from PubMedAlzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-beta plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation. Discovery of 5âAzaindole Inhibitors of OâGlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies.,Bouton J, Bretteville A, Tresadern G, Shaffer P, Austin N, Buijnsters P, Cedervall EP, Darville N, Fonteyn I, Leenaerts J, Lamenca CM, Mertens L, Peeters D, Velter AI, Roosbroeck YV, Ebneth A, Bartolome JM, Trabanco AA, Oehlrich D ACS Med Chem Lett. 2026 Apr 23;17(5):1096-1105. doi: , 10.1021/acsmedchemlett.6c00017. eCollection 2026 May 14. PMID:42157845[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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