Affiliation:
1. Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
2. Department of Orthopaedics, Fuyang People’s Hospital Affiliated to Anhui Medical University, Anhui, China
Abstract
Abstract:
Glycogen synthase kinase-3 (GSK3) is one of the important serine/threonine protein kinases
and has two isoforms, namely, GSK3α and GSK3β. GSK3 inhibits glycogen synthase activity
through phosphorylation. It plays a key role in various pathophysiological processes, such as differentiation,
immunity, metabolism, cell death, and cell survival. Therefore, GSK3 has evolved as an
important therapeutic target for treating neurological diseases, inflammatory diseases, and cancer. In
addition, GSK3 regulates inflammatory processes through NF-κB-induced expression of various
cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Moreover,
GSK3 is reported to participate in many signaling pathways related to disease pathology, including
PI3K/Akt, Wnt, Hedgehog, cyclic adenosine monophosphate, mitogen-activated protein kinase, and
transforming growth factor-β (TGF-β). GSK3 has become a therapeutic target against some inflammatory
diseases, including the inclusion body myositis, sepsis, and inflammatory bowel disease.
Hence, several GSK3 inhibitors have been under evaluation as new therapeutic strategies in recent
years. Two drugs targeting GSK3 have already entered clinical studies, including tideglusib and lithium
carbonate. In this study, we analyzed nearly 30 different small-molecule GSK3 inhibitors reported
in the past 4 years and classified them into four categories (thiazole, pyridine, F-substituted
benzene, and others) according to their structure to conduct further literature research. Moreover, we
summarized the optimal compounds and described the process of transformation from the lead compound
to the optimal compound. In addition, we aimed to summarize the role of GSK3 in the pathogenesis
of inflammatory diseases, with insights into the recent progress in the discovery of GSK3
inhibitors.
Funder
Suzhou Science and Technology Foundation
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmacology,General Medicine