Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
Department of Orthopaedics, Fuyang People's Hospital Affiliated to Anhui Medical University, Anhui, China.
Mini Rev Med Chem. 2023;23(19):1893-1904. doi: 10.2174/1389557523666230412083123.
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.
糖原合成酶激酶-3（GSK3）是一种重要的丝氨酸/苏氨酸蛋白激酶，有两种同工酶形式，即 GSK3α 和 GSK3β。GSK3 通过磷酸化抑制糖原合酶的活性。它在多种病理生理过程中发挥关键作用，如分化、免疫、代谢、细胞死亡和细胞存活。因此，GSK3 已成为治疗神经退行性疾病、炎症性疾病和癌症的重要治疗靶点。此外，GSK3 通过 NF-κB 诱导多种细胞因子（包括肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β和 IL-6）的表达来调节炎症过程。此外，据报道，GSK3 参与与疾病病理相关的许多信号通路，包括 PI3K/Akt、Wnt、Hedgehog、环磷酸腺苷、丝裂原活化蛋白激酶和转化生长因子-β（TGF-β）。GSK3 已成为一些炎症性疾病的治疗靶点，包括包涵体肌炎、脓毒症和炎症性肠病。因此，近年来，已有几种 GSK3 抑制剂被评估为新的治疗策略。两种针对 GSK3 的药物已进入临床研究，包括 tideglusib 和碳酸锂。在这项研究中，我们分析了过去 4 年中报道的近 30 种不同的小分子 GSK3 抑制剂，并根据其结构将它们分为四类（噻唑、吡啶、F 取代苯和其他），以进行进一步的文献研究。此外，我们总结了最佳化合物，并描述了从先导化合物到最佳化合物的转化过程。此外，我们旨在总结 GSK3 在炎症性疾病发病机制中的作用，并深入了解 GSK3 抑制剂发现的最新进展。
