Selective INhibition of DYRK1A kinase for neurodeGEneration – SINGE

Incidence of chronic neurodegenerative disorders like Alzheimer's disease is estimated to double by 2030 and triple by 2050 with the global ageing of population while there is still no curative treatment yet. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) overexpression is correlated with an increased generation of neurofibrillary tangles and amyloid plaques, two main causes of Alzheimer's disease onset, and is therefore appearing as an interesting therapeutic target. DYRK1A inhibition requires a high degree of selectivity over closely related kinases to evaluate its potential as a target to treat Alzheimer's disease. To be considered as potential therapeutics, inhibitors also need to penetrate in the central nervous system to be active in vivo. In this project, we propose to design selective and brain penetrating inhibitors by combining heterocyclic molecules targeting the ATP binding pocket of DYRK1A with substrate mimicking peptidic moieties.