Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII)-targeted drug discovery: Challenges and strategies

Calcium (Ca²⁺)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region. These characteristics of CaMKII make the development of selectively targeted inhibitors particularly challenging. Current CaMKII inhibitors can be classified into the following categories: CaM-binding site blockers (KN62, KN93); ATP-competitive inhibitors (AS105, GS-680, RA306, RA608, SMP-114, NP202, hesperadin); substrate-binding site blockers (AIP, AC3-I, CN21); and pathway-targeted novel modulators (e.g., Athycaltide-1). However, no CaMKII inhibitor has yet reached clinical approval. Nevertheless, CaMKII remains a compelling target due to its pivotal role in age-related pathologies. Several innovative approaches hold promise for overcoming current limitations, including: activating endogenous degradation of CaMKII by proteolysis-targeting chimeras (PROTACs), applying novel materials such as peptide- or nucleic acid-based agents and CRISPR-Cas9-mediated gene editing approaches, employing tissue-specific delivery systems and engineered drug molecules, and targeting disease-specific signaling pathways. Together, these strategies may pave the way for more precise and effective CaMKII-targeted interventions in aging-associated diseases.