Advances in the Therapeutic Potential of Inhibitors Targeting Glycogen Synthase Kinase 3 in Inflammatory Diseases

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.

Keywords: GSK3α; GSK3β; Glycogen synthase kinase-3; inflammatory diseases; inhibitors; small-molecule compound; structure- activity relationship.