azd2858 and Alzheimer-Disease

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC

Topics: Alzheimer Disease; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Humans; Molecular Structure; Neuroprotective Agents; Proteolysis; Structure-Activity Relationship

Glycogen synthase kinase-3β, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3β localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.

Topics: 3T3 Cells; Alzheimer Disease; Animals; Blood-Brain Barrier; Caco-2 Cells; Cattle; Crystallography, X-Ray; Drug Design; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Mice; Models, Molecular; Molecular Structure; Permeability; Phosphorylation; Pyrazines; Solubility; Sulfonamides; tau Proteins