Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Atabecestat Leads to Protein Adduct Formation on Glutathione S-Transferase Pi

Exposure to atabecestat is associated with liver injury, which subsequently led to its withdrawal from development. Previous studies of patients with atabecestat induced liver injury identified T cells responsive to atabecestat and its metabolites, indicating that immune-mediated mechanisms are involved. As irreversible protein modification is suspected to drive immunogenicity, this study aimed to characterize potential atabecestat protein adducts using HSA, GSTA1, and GSTP as model proteins. We have shown that atabecestat only formed a cysteine adduct on GSTP in the presence of metabolic systems, highlighting the important role of bioactivation in adduct formation and selectivity for the binding interaction.