Reduction of Tau phosphorylation via novel OGA inhibitors

O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins, is markedly decreased in Alzheimer's disease (AD) cerebrum. The decrease in O-GlcNAc correlates negatively with phosphorylation at most phosphorylation sites leading to hyperphosphorylation of certain proteins. One such example is the microtubule-associated protein tau, known to play a crucial role in the neurofibrillary degeneration of AD, where hyperphosphorylation leads to the generation of toxic aggregates. The reciprocal relationship between phosphorylation and O-GlcNAcylation of tau and the observed reduction in O-GlcNAcylated tau in AD brain suggests that the generation of inhibitors of O-GlcNAc hydrolysing enzyme OGA offers a novel therapeutic approach to protect neurons in AD brain. It has been shown that inhibition of OGA can effectively enhance O-GlcNAcylation at pathologically relevant sites in rat cortex and hippocampus, reducing tau phosphorylation and resulting aggregates. The primary aim is to develop potent, selective bioavailable inhibitors of OGA as a potential method for altering disease progression for AD and related tauopathies. This has been achieved through application of Summit's proprietary second generation iminosugar (Seglinâ, ™) technology and utilization of its unique in-house expertise in iminosugar chemistry and biology. We have identified inhibitors of recombinant human OGA and generated lead compounds through a rationally designed lead optimisation program. These compounds are very selective, low-nanomolar inhibitors of OGA (Table 1). Treatment of neuronal cells in vitro with the compounds demonstrates increased cellular GlcNAcylation resulting in a significant lowering of the levels of phosphorylated tau, with little evidence of toxicity. Optimisation of compounds for delivery to relevant tau disease models is on-going.