Protein Kinases: Classification, Structural Dynamics, Signalling Mechanisms and Therapeutic Targeting

Abstract

Protein kinases constitute one of the largest and most functionally diverse enzyme families, orchestrating a multitude of cellular processes through reversible phosphorylation of target proteins. The human kinome, encompassing more than 500 kinases, exhibits a highly conserved catalytic core but remarkable structural and regulatory diversity, enabling precise spatiotemporal control of signalling pathways. Kinases act as molecular switches that translate extracellular and intracellular cues into defined biochemical responses, thereby governing critical cellular events such as proliferation, metabolism, differentiation, and apoptosis. Dysregulation of kinase activity—arising from gene mutations, overexpression, or aberrant feedback mechanisms—underlies the pathogenesis of numerous human diseases including cancer, metabolic disorders, neurodegeneration, and inflammation. The therapeutic exploitation of kinases has led to the successful development of small-molecule inhibitors and monoclonal antibodies, with recent advances expanding toward covalent inhibitors, allosteric modulators, and PROTAC-based degraders. Despite these achievements, major challenges persist in achieving selectivity, minimizing toxicity, and circumventing acquired resistance. This review provides a comprehensive overview of kinase classification, structure, and signalling mechanisms, highlights their biological and pathological roles, and discusses emerging strategies and future directions in kinase-targeted drug discovery.