Developments in the design and therapeutic applications of GSK3β inhibitors.

Glycogen synthase kinase-3β (GSK3β) has emerged as one of the most thoroughly validated therapeutic targets in modern drug discovery, with dysregulation implicated in neurodegenerative diseases, metabolic disorders, cancer, psychiatric conditions, and inflammatory pathologies. This review provides a comprehensive and critical overview of recent advances in GSK3β inhibitor design, encompassing ATP-competitive compounds, non-ATP-competitive modulators, covalent inhibitors, and targeted protein degradation strategies. We integrate computational approaches-including pharmacophore modeling, molecular dynamics simulations, and emerging artificial intelligence methods-with experimental validation, distinguishing this work from prior reviews. Therapeutic applications across Alzheimer's disease, type 2 diabetes, cancer, bipolar disorder, and inflammatory conditions are critically examined, with particular emphasis on clinical trial outcomes and translational challenges. We analyze why clinical translation has lagged, identifying insufficient CNS penetration, inadequate target engagement validation, and suboptimal patient selection as key factors, and provide recommendations for future development. Emerging directions including isoform-selective inhibition, context-dependent modulation, combination therapies, and biomarker-driven strategies are discussed. This review offers an integrated perspective on the GSK3β inhibitor landscape and outlines actionable opportunities for developing next-generation therapeutics.