MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

by Selleckchem | Oct 31 2023

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

Comments:

The deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is a hallmark of Alzheimer's disease and other tauopathies. Tau protein can undergo O-linked N-acetylglucosamine (O-GlcNAc) modification, and this modification has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for removing O-GlcNAc moieties, has emerged as a novel approach to mitigate the formation of pathological tau.

In this context, a selective OGA inhibitor called MK-8719 has been investigated for its pharmacological properties both in vitro and in vivo. In vitro studies have demonstrated that MK-8719 is a potent inhibitor of human OGA enzyme activity, and it exhibits comparable activity against OGA enzymes from mouse, rat, and dog. In vivo experiments involving oral administration of MK-8719 have shown dose-dependent elevation of O-GlcNAc levels in the brain and peripheral blood mononuclear cells.

Moreover, positron emission tomography (PET) imaging studies have provided evidence of robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. The rTg4510 mouse model represents human tauopathy. In this model, MK-8719 treatment significantly increases O-GlcNAc levels in the brain and reduces the presence of pathologic tau. Furthermore, the reduction in tau pathology is accompanied by a mitigation of brain atrophy, including a decrease in forebrain volume loss as observed through volumetric magnetic resonance imaging analysis.

These findings suggest that OGA inhibition may be a promising therapeutic strategy for reducing tau pathology in tauopathies such as Alzheimer's disease. However, it is important to note that chronic elevation of O-GlcNAc levels in vivo may influence numerous other O-GlcNAcylated proteins. Therefore, it is crucial to gain a comprehensive understanding of the physiological and toxicological consequences associated with sustained O-GlcNAc elevation in order to fully assess the therapeutic potential and safety of OGA inhibition.

In summary, MK-8719, a potent and selective OGA inhibitor, demonstrates efficacy in elevating O-GlcNAc levels, reducing pathological tau, and ameliorating brain atrophy in a mouse model of tauopathy. These findings indicate that OGA inhibition holds promise as a therapeutic strategy for the treatment of Alzheimer's disease and other tauopathies.