Aboushady, YoussefGabr, MoustafaElHady, Ahmed KSalah, MohamedAbadi, Ashraf HWilms, GerritBecker, WalterAbdel-Halim, MohammadEngel, Matthias2021-11-052021-11-0511/02/2021https://doi.org/10.1021/acschemneuro.1c00475https://bit.ly/3nXfAgVMultiple factors are causally responsible and/or contribute to the progression of Alzheimer’s and Parkinson’s diseases. The protein kinase Dyrk1A was identified as a promising target as it phosphorylates tau protein, α-synuclein, and parkin. The first goal of our study was to optimize our previously identified Dyrk1A inhibitors of the 6-hydroxy benzothiazole urea chemotype in terms of potency and selectivity. Our efforts led to the development of the 3-fluorobenzyl amide derivative 16b, which displayed the highest potency against Dyrk1A (IC50 = 9.4 nM). In general, the diversification of the benzylamide moiety led to an enhanced selectivity over the most homologous isoform, Dyrk1B, which was a meaningful indicator, as the high selectivity could be confirmed in an extended selectivity profiling of 3b and 16b. Eventually, we identified the novel phenethyl amide derivative 24b as a triple inhibitor of Dyrk1A kinase activity (IC50 = 119 nM) and the aggregation of tau and α-syn oligomers. We provide evidence that the novel combination of selective Dyrk1A inhibition and suppression of tau and α-syn aggregations of our new lead compound confers efficacy in several established cellular models of neurotoxic mechanisms relevant to neurodegenerative diseases, including α-syn- and 6-hydroxydopamine-induced cytotoxicities.en-USParkinson’s diseaseDyrk1Amulti-target-directed inhibitor6-hydroxydopamineα-synuclein fibrillationtau oligomerizationArticlehttps://doi.org/10.1021/acschemneuro.1c00475