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Development of inhibitors targeting glycogen synthase kinase-3β for human diseases: Strategies to improve selectivity
Junxia Wei1, Jiaxing Wang2, Jifa Zhang1
1Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Abstract:
Glycogen synthase kinase-3β (GSK-3β) is a conserved serine/threonine kinase that participates in the transmission of multiple signaling pathways and plays an important role in the occurrence and development of human diseases, such as metabolic diseases, neurological diseases and cancer, making it to be a potential and promising drug target. To date, copious GSK-3β inhibitors have been synthesized, but only few have entered clinical trials. Most of them exerts poor selectivity, concomitant off-target effects and side effects. This review summarizes the structural characteristics, biological functions and relationship with diseases of GSK-3β, as well as the selectivity profile and therapeutic potential of different categories of GSK-3β inhibitors. Strategies for increasing selectivity and reducing adverse effects are proposed for the future design of GSK-3β inhibitors.
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