Elevated DYRK1A in Primary Tauopathies and Therapeutic Targeting with the Brain-Penetrant Inhibitor DYR533.

Neurodegenerative disorders are increasing in prevalence, yet disease-modifying therapies remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates tau and regulates inflammatory signaling, making it a potential therapeutic target for neurodegenerative diseases. To investigate the relevance of DYRK1A to primary tauopathies, we first evaluated DYRK1A protein levels in the superior frontal gyrus of individuals with Pick's disease, corticobasal degeneration, and progressive supranuclear palsy. DYRK1A protein expression was significantly elevated in individuals with primary tauopathies compared with healthy controls and positively correlated with Braak stage. Conversely, DYRK1A levels inversely correlated with last Mini-Mental State Examination (MMSE) scores and brain weight, linking elevated DYRK1A expression to disease severity. We next developed DYR533, a selective, orally bioavailable, brain-penetrant small-molecule DYRK1A inhibitor with an S(35) score of 1.4 nM based on a 403-target KINOMEscan assay. Mechanistically, DYR533 prevented the autophosphorylation of newly translated DYRK1A, rendering the kinase inactive and thereby inhibiting phosphorylation of downstream substrates. We next evaluated the therapeutic efficacy of DYR533 in the PS19 mouse model of primary tauopathy, assessing tau hyperphosphorylation, neuroinflammation, motor function, and spatial cognition. DYR533 reduced tau hyperphosphorylation at threonine 217, threonine 181, and serine 396, and attenuated the expression of neuroinflammatory cytokines and chemokines implicated in disease progression. In PS19 mice, DYR533 treatment produced modest improvements on behavior. Together, these findings establish an association between elevated DYRK1A and disease severity in human primary tauopathies and demonstrate that pharmacological inhibition of DYRK1A with DYR533 reduces pathological tau phosphorylation and neuroinflammatory signaling in vivo.