The progressive accumulation of the microtubule-associated protein tau in the brain is a characteristic hallmark of Alzheimer's disease (AD) and other tauopathies. Post-translational modifications of tau by O-linked-b-N-acetyl-glucosamine (O-GlcNAc) are inversely related to the levels of its insoluble hyper-phosphorylated form. The tau O-GlcNAc modification is regulated by the action of two enzymes, O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). Increased tau O-GlcNAcylation reduces tau aggregation and studies have found that OGA inhibition decreased the accumulation of hyperphosphorylated, aggregated tau in different tau-overexpression mice. This presentation will describe the discovery and early clinical development of LY3372689, a potent OGA inhibitor capable of achieving enzyme occupancy &gt; 90% in humans at low doses.

Discovery and early clinical development of LY3372689, an O-GlcNAcase (OGA) enzyme inhibitor

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.