O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer’s disease and related tauopathies: analysis of the patent literature

ABSTRACT

Introduction: O-GlcNAcylation is a highly abundant post-translational modification of multiple proteins, including the microtubule-binding protein tau, governed by just two enzymes’ concerted action O-GlcNAc transferase OGT and the hydrolase OGA. It is an approach to reduce abnormal tau hyperphosphorylation and aggregation in Alzheimer’s disease (AD) and related tauopathies based on the ability of O-GlcNAcylation competing with tau phosphorylation, thus minimizing aggregation. The preclinical validation confirmed OGA inhibitors’ efficacy in different transgenic tau mice models. Only three other OGA inhibitors have advanced into clinical trials thus far.

Areas covered: 2008–2020 patent literature on OGA inhibitors.

Expert opinion: Neurodegenerative disorders and AD specifically represent an enormous challenge since no effective treatments are available. Promising preclinical data has prompted considerable interest in searching for OGA inhibitors as a potential treatment for neurodegenerative disorders. Efforts from different companies have yielded a diverse set of chemotypes. OGA is a highly ubiquitous enzyme with many client proteins, generated data confirms a promising benign profile for OGA inhibition in healthy volunteers. Additionally, OGA PET tracers’ existence will be critical for proper dose selection for future PoC Phase II studies, which will proof the true potential of OGA inhibition for the treatment of AD and other tauopathies.

KEYWORDS:

• O-GlcNAcase
• OGA; tau
• Alzheimer’s disease
• tauopathies

Article highlights

• O-GlcNAcylation is a highly abundant post-translational modification of multiple proteins. It includes the concerted action of O-GlcNAc transferase OGT and the hydrolase OGA.

• In Alzheimer’s disease (AD) and related tauopathies, tau gets hyperphosphorylated and aggregates into neurofibrillary tangles. The extent, the spreading pattern and the concentration of neurofibrillary tangles correlate with neurodegeneration severity. In vitro, increased O-GlcNAcylation reduces tau aggregation’s extent and speed, and O-GlcNAcylation can compete with phosphorylation.

• Extensive preclinical validation, using relevant tau transgenic models, has confirmed robust in vivo efficacy for the highly potent and brain penetrant OGA tool compound Thiamet G.

• OGA inhibition has emerged as a novel potential therapeutic target for treating AD and related neurodegenerative diseases.

• Three OGA inhibitors have entered clinical trials: MK-8719 from Merck/Alectos, ASN-120,290 from Asceneuron S.A. and LY-3,372,689 from Eli Lilly.

• Released data suggests a benign side effect profile for MK-8719 and ASN-120,290 and confirmed target engagement in the brain for MK-8719.

• Phase II PoC studies are still pending to undoubtedly support the great promises that OGA inhibition holds for treating AD and related tauopathies.

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Declaration of interest

All authors are employees of Janssen Research and Development. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an employee of Alectos Therapeutics, which is engaged in developing OGA inhibitors as therapeutics. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.