Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)
Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)
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DOI：
10.1016/j.bmc.2018.09.027
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发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Chu, Yong
中科院分区：
文献类型：
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作者：
Gao, Yang;Zhang, Peng;Chu, Yong
糖原合成酶-3β(GSK-3β)已被证实具有促炎作用，其抑制剂在动物模型中也被证明可以治疗一些炎症性疾病。非三磷酸腺苷竞争性抑制剂因其比三磷酸腺苷竞争性抑制剂具有更高的特异性而具有更好的治疗价值。本论文设计并合成了一系列新型的BTZ类非ATP竞争性GSK-3β抑制剂。动力学分析表明，两个典型的化合物6J和3J分别对GSK-3β具有不同的底物竞争或变构调节的非ATP竞争机制。不出所料，这两个化合物在16个蛋白激酶的小组测试中表现出了良好的特异性，甚至对最接近的酶，如CDK-1/Cyclin B和CK-II也表现出良好的特异性。体内实验结果表明，两种化合物均可通过抑制IL-1β和IL-6mRNA的表达，显著减轻内毒素诱导的小鼠急性肺损伤(ALI)，减轻炎症反应。Western印迹分析表明，它们对GSK-3β具有负性调节作用，其作用机制可能与增加GSK-3β上Ser9残基的磷酸化和Sirtuin 1(SIRT1)的蛋白表达有关。结果表明，这些新的BTZ化合物对脂多糖诱导的ALI具有保护作用，并可能成为进一步发展炎症药物治疗的有吸引力的候选药物，这在很大程度上要归功于它们通过非ATP竞争性作用方式固有的高选择性。最后，我们通过对接研究提出了结合模式的建议，以更好地解释化合物对靶位的影响。
Glycogen synthase kinase-3 beta (GSK-3 beta) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3 beta inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3 beta, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1 beta and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3 beta, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3 beta and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.