DYRK1

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is a serine/threonine kinase that regulates neuronal differentiation, synaptic plasticity, and cell cycle progression^[1][4]. Mechanistically, DYRK1A modulates pre- and post-synaptic signaling and alternative splicing, thereby influencing neuronal development and adult cognitive function^[3][1]. DYRK1A activity affects cytoskeletal dynamics through MKL1-mediated pathways, promoting morphogenesis in human neonatal megakaryocytes^[2]. Overexpression or dosage imbalance of DYRK1A contributes to neurodevelopmental disorders such as Down syndrome and MRD7, and to neurodegenerative diseases including Alzheimer’s and Parkinson’s disease^[1][4][5]. Compared with related isoforms DYRK1B and DYRK2, DYRK1A uniquely regulates central nervous system processes, including tau phosphorylation and APP processing, while DYRK1B predominantly modulates stem cell behavior and metabolic pathways^[1][6][7]. Pharmacologically, small molecule inhibitors such as harmine, AnnH75, and thiazoloquinazolines selectively target DYRK1A, enabling modulation of neuronal differentiation, alternative splicing, and pathological tau phosphorylation, with minimal off-target activity^[3][4][6][8]. Agonists and inhibitors of DYRK1A also facilitate experimental studies of megakaryocyte morphogenesis, bipolar androgen therapy in prostate cancer, and CNS-related cellular senescence^[2][9]. Structural studies reveal that inhibitor binding exploits ATP-competitive mechanisms and hinge region interactions, supporting development of isoform-selective chemical probes for translational research^[8].