ZJCK-6-72

ZJCK-6-72 is a preclinical, orally bioavailable, and brain-penetrant small-molecule inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Developed by China Medical University, the General Hospital of Northern Theater Command, and Shenyang Pharmaceutical University, it was designed as an optimized successor to ZJCK-6-46 to improve blood-brain barrier permeability and reduce P-glycoprotein (P-gp) efflux liability. ZJCK-6-72 binds to the hinge region of the DYRK1A ATP pocket with an IC50 of 8.64 nM. By inhibiting DYRK1A, it blocks the activation of NF-κB and the NLRP3 inflammasome, thereby reducing the release of pro-inflammatory cytokines (such as TNF-α and IL-6), nitric oxide (NO) levels, and pyroptosis. It is being investigated as a lead candidate for the treatment of Alzheimer's disease and associated neuroinflammation.