ZJCK-6-46 is a potent, selective, and orally available dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitor with IC50 of 0.68 nM.
ZJCK-6-46 significantly inhibits the activity of DYRK1B (IC50=1.02 nM), shows weak activity against other three DYRK isoforms(DYRK2, IC50 = 14.18 nM; DYRK3, IC50 = 17.48 nM; DYRK4, IC50 = 401.3 nM).
ZJCK-6-46 also inhibits the activities of CLKs, especially, CLK1 and CLK4 (IC50 = 1.68 and 1.80 nM, respectively), while CLK3 shows relatively less sensitiveness (IC50 = 38.91 nM).
ZJCK-6-46 significantly decreases DYRK1A-mediated phosphorylated tau at the Thr212 site (p-Tau Thr212) with EC50 of 11.36 nM in Tau (P301L) 293T cells, EC50 of 16.99 nM in unstimulated, fast-dividing SH-SY5Y cells.
ZJCK-6-46 (20 mg/kg, 30 mg/kg) improved OA-induced cognitive dysfunction by reducing the expression level of phosphorylated tau in OA-induced AD mouse models.