Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 iPSC-derived neural cells.

Dysregulated expression and activity of DYRK1A, dual specificity tyrosine phosphorylation regulated kinase 1A, is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimer's disease, and Parkinson's disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer's disease, for example, but the ability to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell derived neural progenitor cells and neurons, where DYRK1A expression and activity are increased. Our results demonstrate that Leucettinib-21, a potent and selective low-molecular weight pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 neural progenitor cells and cortical neurons. We show for the first time that Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.