Development of Novel Dyrk1a Inhibitors for the Treatment of Alzheimer'S Disease

Alzheimer's disease (AD) is a chronic, irreversible neurodegenerative disorder where patients develop dementia, cognitive disorders and mood changes. The drugs currently used for AD are limited due to lack of efficacy and only slow deterioration. Therefore, it is urgent to find new targets for developing drugs to treat AD patients. Amyloid plaques, an aggregation of beta amyloid protein (Abeta), are one of the two brain abnormalities that define AD. The other hallmark is neurofibrillary tangles (NFT), which are aggregates of hyperphosphorylated tau protein. Previous studies have shown that DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) are highly expressed in the hippocampus of AD patients and involved in the pathogenesis of plaques and NFT formation. Thus, inhibition of DYRK1A is a potential target to treat AD. By using computational modeling analysis, our research team have filtered five potential DYRK1A inhibitors. Three specific aims will be executed in three years: (1) based on these five structures, we will optimize and synthesize potent DYRK1A inhibitors. (2) to validate the inhibitory effect of DYRK1A inhibitors on reduction of Abeta formation and Tau phosphorylation using neuronal cells. (3) to select the most potent compound as our candidate DYRK1A inhibitor and evaluate its effect on learning and memory enhancement in both aging mice, scopolamine induced memory impairment mice and transgenic mice. Our preliminary result showed that one of our five candidates, 711-D-001, inhibit only DYRK1 family out of 97 human kinase families. Further validation experiment showed that 711-D-001 inhibited only DYRK1A but not DYRK1B indicating that this is a highly selective inhibitor against DYRK1A. From this project, a new category of drugs will be developed for the treatment of AD.