Small-molecule inhibitors of GSK3β: Therapeutic potential and structure-activity relationship in multiple systems

Protein kinases (PK) are a class of enzymes that phosphorylate protein molecules and play crucial roles in various biological processes, including cell proliferation, apoptosis, cell cycle regulation, differentiation, and signalling pathways. As essential components of the human body, they have become a major focus in drug development. Consequently, protein kinase inhibitors have emerged as a prominent area of clinical medicine. In recent years, small molecule inhibitors targeting glycogen synthase kinase-3 (GSK3), a representative protein kinase, have been increasingly used in clinical settings. This review comprehensively summarises 26 GSK3β small molecule inhibitors, categorizing them by their therapeutic applications across nine major systemic diseases. It also summarises the structure-activity relationships of several common compounds and examines, through molecular docking, the protein-binding capabilities of highly selective and specific inhibitors, many of which are already in clinical use or nearing clinical entry. By proposing promising research directions and establishing a solid foundation, this work paves the way for developing GSK3β small molecule inhibitors tailored to diverse diseases.