Dyrk1A-IN-17

Dyrk1A-IN-17 is an orally active multikinase inhibitor capable of crossing the blood-brain barrier. It reduces the hyperphosphorylation of α-synuclein by inhibiting four kinases: ABL1, DYRK1A, GSK3β, and LRRK2, while stabilizing microtubules. Dyrk1A-IN-17 is applicable in the research of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

Dyrk1A-IN-17 (Compound 1) at a concentration of 10 μM moderately inhibits the activity of four kinases—ABL1, DYRK1A, GSK3β, and LRRK2—in in vitro kinase inhibition assays, with average inhibition rates of 56.5%, 48%, 61%, and 59%, respectively. At 100 μM, Dyrk1A-IN-17 reduces the binding between Colchicine and tubulin by 34%. When used at 50 μM, it inhibits the binding of Vinblastine to tubulin by 15%. Additionally, Dyrk1A-IN-17 within a range of 4-8 μM over 10 days can decrease pSer129 hyperphosphorylation induced by α-synuclein fibrils, nuclear fragmentation, and condensation in primary rat hippocampal cell cultures, while slightly increasing levels of acetylated α-tubulin.

Dyrk1A-IN-17 (5 mg/kg; oral administration) can moderately reduce the excessive phosphorylation levels of insoluble α-synuclein in the central nervous system of mice with preformed fibril infusion.