Résumé
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.