Unlocking the therapeutic potential of protein kinase inhibitors in neurodegenerative and psychiatric disorders

Protein phosphorylation is a fundamental regulatory mechanism governing a broad spectrum of cellular processes. In the nervous system, it is critical for modulating neurotransmitter release, synaptic plasticity, neuronal excitability, and cell survival. Dysregulation of protein kinase activity is closely linked to the pathogenesis of various neurological and psychiatric disorders, positioning several kinases as promising therapeutic targets. Although protein kinase inhibitors (PKIs), a major class of compounds that modulate kinase activity, have shown considerable therapeutic success in oncology, their application in neurological diseases remains in the early stages of exploration. Of the 82 PKIs approved by the Food and Drug Administration (FDA), 37 are now in various preclinical and clinical trials for neurological conditions, primarily targeting signaling pathways mediated by key protein kinases implicated in these diseases. This review examines the roles of critical protein kinases and the therapeutic effects of their inhibitors in neurodegenerative, psychiatric, and selected neurological disorders, such as autism spectrum disorders (ASD) and epilepsy. We focus on Abelson kinase I (ABL1), calmodulin-dependent kinase II (CaMKII), casein kinase 1δ (CK1δ), c-Jun N-terminal kinase (JNK), cyclin-dependent kinase 5 (CDK5), dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A), leucine-rich repeat kinase 2 (LRRK2), extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3β (GSK3β), mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase, and protein kinase C (PKC) in neurodegenerative diseases. Additionally, we discuss CaMKII, CDK5, ERK1/2, PI3K/AKT/GSK3, protein kinase A (PKA), and PKC in psychiatric disorders, focusing on schizophrenia and mood disorders, and analyze GSK3β, ERK1/2, and mTOR in ASD and epilepsy. This review underscores the therapeutic potential of PKIs in neurological disorders while highlighting ongoing challenges and the need for further research to refine kinase-targeted therapies.