Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Biochem Pharmacol. 2013 Apr 1;85(7):965-76. doi: 10.1016/j.bcp.2012.12.023. Epub 2013 Jan 18.
Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of β-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment.
糖原合酶激酶 3（GSK-3）在细胞能量代谢中发挥核心作用，GSK-3 活性失调与多种代谢紊乱有关，包括肥胖、2 型糖尿病和癌症。因此，GSK-3 已成为治疗代谢紊乱的有吸引力的靶标分子。因此，本研究集中于鉴定和表征新型小分子 GSK-3 抑制剂。化合物 1a 是一种基于带有异噻唑烷-1,1-二酮的 3-羟基色酮的结构，从化学文库中被鉴定为一种高效的 GSK-3 抑制剂。利用一组激酶进行的体外激酶测定表明，化合物 1a 强烈抑制 GSK-3β。在人肝 HepG2 和人胚肾 HEK293 细胞中，通过化合物 1a 确认了对 GSK-3 失活的潜在影响。与另外两种 GSK-3 抑制剂：LiCl 和 SB-415286 相比，化合物 1a 对糖原合酶和 GSK-3 的直接靶标β-catenin 的稳定作用进行了评估。在小鼠 3T3-L1 前脂肪细胞中，化合物 1a 显著阻止脂肪细胞分化。一致地，化合物 1a 腹腔内给药可显著改善饮食诱导肥胖小鼠的关键症状，如体重增加、脂肪增加、血脂异常和肝脂肪变性，因为全身脂质水平显著降低。体外和体内作用伴随着β-catenin 稳定性的上调和与脂质代谢相关的几个关键基因的表达下调。从这些结果可以得出结论，化合物 1a 是一种新型 GSK-3 小分子抑制剂，具有作为肥胖治疗的新型治疗剂的潜力。
