O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies
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these have been shown to prevent its aggregation and toxicity. Here, we report the preclinical discovery and development of a novel small molecule OGA inhibitor, ASN90. Consistent with the substantial exposure of the drug and demonstrating target engagement in the brain, the clinical OGA inhibitor ASN90 promoted the O-GlcNAcylation of tau and α-synuclein in brains of transgenic mice after daily oral dosing. Across human tauopathy mouse models, oral administration of ASN90 prevented the development of tau pathology (NFT formation), functional deficits in motor behavior and breathing, and increased survival. In addition, ASN90 slowed the progression of motor impairment and reduced astrogliosis in a frequently utilized α-synuclein-dependent preclinical rodent model of PD. These findings provide a strong rationale for the development of OGA inhibitors as disease-modifying agents in both tauopathies and α-synucleinopathies. Since tau and α-synuclein pathologies frequently co-exist in neurodegenerative diseases, OGA inhibitors represent unique, multimodal drug candidates for further clinical development.
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Inhibitors of O-GlcNAcase enzyme (OGA) like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice.
“Inhibitors of the O-GlcNAcase enzyme (OGA)-like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice [174, 220, 221].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [221]
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- Authors
- Permanne, B., Sand, A., Ousson, S., Nény, M., Hantson, J., Schubert, R., Wiessner, C., Quattropani, A., & Beher, D.
- Affiliations
- Asceneuron (Switzerland) (CH)
- Corresponding author
- Beher, Dirk
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-03-31
- Volume
- 13
- Issue
- 8
- Pages
- 1296-1314
- ISSN
- 1948-7193 (ISSN-L)
- PMC
- PMC9026285
- OpenAlex
- W4221137705
- Cited by
- 82
- References
- 66
- Citations by year
- 2026: 12 · 2025: 29 · 2024: 22 · 2023: 15 · 2022: 4
- FWCI
- 10.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- ACS Chemical Neuroscience (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation (20131210)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- O-GlcNAcase inhibitors, O-GlcNAcylation, tauopathy, synucleinopathies, Parkinson's disease, tau aggregation, neurofibrillary tangles, astrocyte activation, motor impairment, oral drug delivery, disease-modifying therapy
- MeSH terms
- Synucleinopathies, Animals, beta-N-Acetylhexosaminidases, Pharmaceutical Preparations, Parkinson Disease, tau Proteins, Tauopathies, Mice, alpha-Synuclein
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