Abstract by Christos Avgerinos

Targeted protein degradation (TPD) has emerged in the field of drug discovery as a powerful event-driven pharmacological approach, enabling selective degradation of a protein of interest in a catalytic mode of action. PROteolysis TArgeting Chimeras (PROTACs) and Chaperone-Mediated Autophagy TArgeting Chimeras (CMATACs) are heterobifunctional molecules that exploit this strategy to induce proteasomal and lysosomal degradation, respectively.

Calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), predominantly expressed in excitatory synapses, plays a pivotal role in long term potentiation (LTP) and exhibits pathological hyperactivity under ischemic conditions, underscoring its pharmacological relevance. Although in house series of potent CaMKIIα hub ligands have already been developed, such chimeric degraders could offer unique tools to elucidate CaMKIIα downstream signaling implications and therapeutic potential.