Integrative Insights Into DYRK1A From Molecular Function to Therapeutic Advancement

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), located within the Down syndrome critical region and implicated in Alzheimer's disease (AD), Parkinson's disease (PD), and context-dependent cancer biology, represents a high-value yet challenging therapeutic target. This review compiles comprehensive structure-activity relationship (SAR) insights essential for medicinal chemists designing selective DYRK1A inhibitors. We detail the molecular architecture of the ATP-binding pocket of DYRK1A, key regulatory residues (Lys188, Phe238, Glu239, Leu241), and structure-function relationships governing inhibitor classes: ATP-competitive agents, ATP-non-competitive inhibitors, and Proteolysis-Targeting Chimeras (PROTAC) degraders with emphasis on functional group modifications and scaffold optimization strategies. Readers will gain actionable insights on binding mode predictions, potency-selectivity trade-offs, and prioritization of lead compounds for preclinical validation. The framework addresses pharmacokinetic property optimization and selectivity profiling across kinase families, enabling researchers to accelerate rational inhibitor design and facilitate translation of DYRK1A therapeutics into clinical trials for neurodegenerative and developmental disorders.