Structure-BasedVirtual Screening Identifies 2‑Arylthiazole-4-CarboxylicAcids as a Novel Class of Nanomolar Affinity Ligands for the CaMKIIαHub Domain

The Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) plays a crucial role in regulating neuronal signaling and higher brain functions, being involved in various brain diseases. Utilization of small molecules targeting the CaMKIIα hub domain has proved to be a promising strategy for specific CaMKIIα modulation and future therapy. Through an <i>in silico</i> structure-based virtual screening campaign, we herein identified 2-arylthiazole-4-carboxylic acids as a new class of high-affinity CaMKIIα hub ligands. Particularly, the 2,6-dichlorophenyl analog, PTCA (compound <b>1a</b>), displayed mid-nanomolar affinity (p<i>K</i>_i = 7.2) and substantial stabilization of the CaMKIIα hub oligomer upon binding. Moreover, the <i>tert</i>-butyl ester prodrug, <b>14a</b>, was developed to facilitate the brain delivery of PTCA and demonstrated remarkable enhancement in brain penetration compared to PTCA <i>per se</i> after systemic administration. Altogether, our study highlights that PTCA represents a novel and powerful tool compound for future pharmacological interventions targeting CaMKII kinase in the brain.