Development of inhibitors targeting glycogen synthase kinase-3β for human diseases: Strategies to improve selectivity

Junxia Wei; Jiaxing Wang; Jifa Zhang; Jinliang Yang; Guan Wang; Yuxi Wang

doi:10.1016/j.ejmech.2022.114301

Development of inhibitors targeting glycogen synthase kinase-3β for human diseases: Strategies to improve selectivity

Eur J Med Chem. 2022 Jun 5:236:114301. doi: 10.1016/j.ejmech.2022.114301. Epub 2022 Mar 31.

Authors

Junxia Wei¹, Jiaxing Wang², Jifa Zhang¹, Jinliang Yang¹, Guan Wang³, Yuxi Wang⁴

Affiliations

¹ Department 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.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States.
³ Department 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. Electronic address: [email protected].
⁴ Department 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; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].

PMID: 35390715
DOI: 10.1016/j.ejmech.2022.114301

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.

Keywords: Cancer treatment; GSK-3β; Inhibitors; Selectivity.

Publication types

Review

MeSH terms

Glycogen Synthase Kinase 3 beta* / antagonists & inhibitors
Humans
Neoplasms* / drug therapy

Substances

Glycogen Synthase Kinase 3 beta