The Discovery of DYR533, a Selective, Orally Bioavailable, Non-Toxic, Brain Penetrant DYRK1A Inhibitor, a Potential Therapeutic for Neurodegenerative Diseases

Abstract

Targeting neurodegenerative disease and Alzheimer’s disease (AD) pathology at specific pathways is clearly impossible, and a successful therapeutic strategy will require pleiotropic interventions. Herein, this thesis articulates an alternative strategy involving targeting of both amyloid and tauopathies through selective inhibition of the dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A), thereby reducing both Amyloid Precursor Protein (APP) and tau phosphorylation events. The hyperphosphorylation of the microtubule stabilizing protein tau contributes to tau dysfunction and aggregation into neurofibrillary tangles (NFTs), which are highly correlated to dementia severity in various neurodegenerative diseases such as Alzheimer's Disease. To this end, this dissertation coalesces work done toward the discovery of DYR533, a selective, orally bioavailable, non-toxic, brain penetrant DYRK1A inhibitor which has great potential therapeutic for the treatment of neurodegenerative diseases.