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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Dysregulated dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is implicated in neurodevelopmental and neurodegenerative diseases.
• DYRK1A inhibitors show therapeutic potential for neurological disorders, but their efficacy in human cells is not well-established.
• Down syndrome is characterized by increased DYRK1A expression and activity.

Purpose of the Study:

• To investigate the effect of a novel DYRK1A inhibitor, Leucettinib-21, on DYRK1A activity in human cells relevant to Down syndrome.
• To establish a human cell model for testing DYRK1A-targeting therapeutics.

Main Methods:

• Utilized trisomy 21 induced pluripotent stem cell (iPSC)-derived neural progenitor cells and neurons.
• Administered Leucettinib-21, a selective low-molecular weight pharmacological inhibitor of DYRK1A.
• Measured the impact of Leucettinib-21 on DYRK1A activity in these human cells.

Main Results:

• Leucettinib-21 significantly decreased DYRK1A activity in human trisomy 21 neural progenitor cells.
• Leucettinib-21 reduced DYRK1A activity in human trisomy 21 cortical neurons.
• Demonstrated the efficacy of Leucettinib-21 in a relevant human disease model.

Conclusions:

• Leucettinib-21 is a potent and selective inhibitor of DYRK1A in human cells.
• This study provides the first evidence of Leucettinib-21 reducing DYRK1A activity in a human iPSC-derived neural cell model of Down syndrome.
• The findings support the potential of Leucettinib-21 for future human clinical trials targeting neurological disorders.