Wagman Allan S, Johnson Kirk W, Bussiere Dirksen E
Medicinal Chemistry, Chiron Corporation, 4560 Horton Street, M/S 4.5, Emeryville, CA 94608-2916, USA.
Curr Pharm Des. 2004;10(10):1105-37. doi: 10.2174/1381612043452668.
Originally identified as a modulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now understood to play an important regulatory role in a variety of pathways including initiation of protein synthesis, cell proliferation, cell differentiation, apoptosis, and is essential for embryonic development as a component of the Wnt signaling cascade. GSK3 can be considered as a target for both metabolic and neurological disorders. GSK3's association with neuronal apoptosis and hyper-phosphorylation of tau make this kinase an attractive therapeutic target for neurodegenerative conditions such as head trauma, stroke and Alzheimer's disease. While noting GSK3's many associated functions, this review will focus on GSK3 as a central negative regulator in the insulin signaling pathway, its role in insulin resistance, and the utility of GSK3 inhibitors for intervention and control of metabolic diseases including type 2 diabetes. Recent crystal structures, including the active (phosphorylated Tyr-216) form of GSK3beta, provide a wealth of structural information and greater understanding of GSK3's unique regulation and substrate specificity. Many potent and selective small molecule inhibitors of GSK3 have now been identified, and used in vitro to modulate glycogen metabolism and gene transcription, increase glycogen synthase activity and enhance insulin-stimulated glucose transport. The pharmacology of potent and selective GSK3 inhibitors (CT 99021 and CT 20026) is described in a number of in vitro and in vivo models following acute or chronic exposure. The efficacy of clinical candidates in diabetic primates and the implications for clinical development are discussed. The profile of activity is consistent with a unique form of insulin sensitization which is well suited for indications such as metabolic syndrome X and type 2 diabetes.
糖原合酶激酶-3（GSK3）最初被鉴定为糖原代谢的调节因子，现在人们认识到它在多种途径中发挥重要的调节作用，包括蛋白质合成的起始、细胞增殖、细胞分化、细胞凋亡，并且作为Wnt信号级联反应的一个组成部分，对胚胎发育至关重要。GSK3可被视为代谢和神经疾病的一个靶点。GSK3与神经元凋亡以及tau蛋白的过度磷酸化有关，这使得该激酶成为头部创伤、中风和阿尔茨海默病等神经退行性疾病颇具吸引力的治疗靶点。在指出GSK3的许多相关功能的同时，本综述将聚焦于GSK3作为胰岛素信号通路中的核心负调节因子、其在胰岛素抵抗中的作用以及GSK3抑制剂在干预和控制包括2型糖尿病在内的代谢疾病中的效用。最近的晶体结构，包括GSK3β的活性（酪氨酸-216磷酸化）形式，提供了丰富的结构信息，并加深了对GSK3独特调节和底物特异性的理解。现在已经鉴定出许多强效且选择性的GSK3小分子抑制剂，并在体外用于调节糖原代谢和基因转录、增加糖原合酶活性以及增强胰岛素刺激的葡萄糖转运。在急性或慢性暴露后的许多体外和体内模型中描述了强效且选择性的GSK3抑制剂（CT 99021和CT 20026）的药理学特性。讨论了临床候选药物在糖尿病灵长类动物中的疗效及其对临床开发的意义。活性特征与一种独特的胰岛素增敏形式一致，这非常适合代谢综合征X和2型糖尿病等适应症。
