This presentation will describe the medicinal chemistry and pharmacological studies leading to identification of the first-in-class clinical O-GlcNAcase (OGA) inhibitor, MK-8719. The development of preclinical pharmacodynamic biomarkers and translation to clinical (Ph I) results will also be presented.<br/><br/>One of the pathological hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies is the accumulation of neurofibrillary tangles (NFTs) in the brain. NFTs are composed primarily of aggregates of the microtubule-associated protein tau. Aggregation of tau appears to be driven by its abnormal hyperphosphorylation leading to self-assembly into the paired helical filaments that make up NFTs. Pathological species of tau are thought to play a central role in driving neuronal cell death in these diseases and the extent of NFT pathology correlates with clinical progression in AD. Emerging evidence also supports the idea that soluble hyperphosphorylated tau species are involved in prion-like propagation of tau pathology throughout the brain in AD. Consequently, major efforts are focused on targeting pathogenic tau species to develop disease-modifying therapies for AD and related tauopathies.<br/><br/>O-GlcNAcylation is a reversible post-translational modification that involves addition of O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues, and is regulated by two enzymes: O-GlcNAc transferase, which catalyzes addition of O-GlcNAc to proteins, and OGA, which catalyzes cleavage of O-GlcNAc from proteins. O-GlcNAcylation of tau has been proposed to regulate its phosphorylation state, with increased O-GlcNAc modification being correlated with lower tau phosphorylation. In addition, in vitro studies indicate that increased O-GlcNAcylation of tau hinders its propensity for aggregation. These data suggest that OGA inhibition could increase O-GlcNAc modification of tau and reduce the formation of pathogenic tau species. Consistent with this idea, multiple independent studies using transgenic murine models of tauopathy have shown that administration of the small-molecule OGA inhibitor Thiamet-G confers beneficial effects, including: reduced phosphorylated tau species and tau aggregates, reduced tau levels in cerebrospinal fluid, decreased neuronal cell loss, and reduced disease-associated behavioral phenotypes. On the basis of these findings, OGA inhibition has emerged as a therapeutic strategy to treat tau pathology in AD and other tauopathies.

Discovery of MK-8719: Potent O-GlcNAcase inhibitor as a potential treatment for tauopathies

2019 Fall National Meeting

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