Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.
Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.
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具有精细全激酶组选择性的糖原合酶激酶 3 抑制剂及其功能效应。
DOI：
10.1021/acschembio.6b00306
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发表时间：
2016
影响因子：
4
通讯作者：
Germain,A
中科院分区：
文献类型：
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作者：
Wagner,FlorenceF;Bishop,JoshuaA;Gale,JenniferP;Shi,Xi;Walk,Michelle;Ketterman,Joshua;Patnaik,Debasis;Barker,Doug;Walpita,Deepika;Campbell,ArthurJ;Nguyen,Shannon;Lewis,Michael;Ross,Linda;Weïwer,Michel;An,WFrank;Germain,A
情绪稳定剂锂是双相情感障碍的一线治疗药物，据推测，锂通过直接抑制糖原合成酶激酶3（GSK 3）和间接增加GSK 3的抑制性丝氨酸磷酸化来发挥其作用。GSK 3包含两个高度相似的旁系同源物，GSK 3 α和GSK 3 β，它们是经典Wnt途径中的关键调节激酶。GSK3是该通路中的节点靶点，是多种适应症的有吸引力的治疗靶点。尽管在过去的20年里是一个活跃的研究领域，但许多GSK 3抑制剂表现出与更广泛的人类激酶组相比的较差至中等的选择性或不适合在体外系统或体内模型中使用的物理化学性质。对来自GSK 3 β抑制剂高通量筛选活动的数据进行非常规分析，排除了已知的GSK 3抑制剂化学型，发现了一种新型吡唑并四氢喹啉酮支架，对GSK 3激酶具有无与伦比的全激酶组选择性。利用与GSK 3铰链区的不常见的三齿相互作用，我们开发了高度选择性和有效的GSK 3抑制剂BRD 1652和BRD 0209，其在多巴胺能信号传导模式建模情绪相关疾病中表现出体内功效。这些新的化学探针为专门分析GSK 3激酶在许多流行疾病中涉及的多种信号通路中的功能开辟了道路。
The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3’s inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use inin vitrosystems orin vivomodels. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors,BRD1652andBRD0209, which demonstratedin vivoefficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.