11LJ

Human OGA IN COMPLEX WITH LIGAND 24

This is a non-PDB format compatible entry.

Summary for 11LJ

• Entry DOI: 10.2210/pdb11lj/pdb
• Descriptor: Protein O-GlcNAcase N-Terminal Fragment, Protein O-GlcNAcase 535-704 Peptide, N,N-dimethyl-2-(4-{[4-methyl-2-(propan-2-yl)pyridin-3-yl]amino}-1H-pyrrolo[3,2-c]pyridin-1-yl)acetamide, ... (5 entities in total)
• Functional Keywords: glycoside hydrolase, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 126907.69

Authors

Shaffer, P.L.,Cedervall, P. (deposition date: 2026-03-03, release date: 2026-07-01)

Primary citation

Bouton, J.,Bretteville, A.,Tresadern, G.,Shaffer, P.,Austin, N.,Buijnsters, P.,Cedervall, E.P.,Darville, N.,Fonteyn, I.,Leenaerts, J.,Lamenca, C.M.,Mertens, L.,Peeters, D.,Velter, A.I.,Roosbroeck, Y.V.,Ebneth, A.,Bartolome, J.M.,Trabanco, A.A.,Oehlrich, D.
Discovery of 5‐Azaindole Inhibitors of O‐GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies.
Acs Med.Chem.Lett., 17:1096-1105, 2026

PubMed Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β 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 was identified as an tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.

PubMed: 42157845
DOI: 10.1021/acsmedchemlett.6c00017

Experimental method

X-RAY DIFFRACTION (2.325 Å)