Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zhengshui Xu, Changchun Ye, Xingjie Wang, Ranran Kong, Zilu Chen, Jing Shi, Xin Chen, Shiyuan Liu
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引用次数: 0

Abstract

A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[d][1, 3]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5-a]pyridin-2-yl)amino)methyl)-N-hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC50 values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.

设计和合成具有广谱抗增殖活性的强效 JAK/HDAC 双抑制剂三唑吡啶衍生物。
通过将不同的药理作用合二为一,合理地设计和合成了一系列基于三唑吡啶的 JAK/HDAC 双重抑制剂。所有三唑并吡啶衍生物对这两个靶点都表现出了强效的抑制活性,其中最好的化合物是 4-(((5-(苯并[d][1, 3]二恶茂-5-基)-[1, 2, 4]三唑并[1, 5-a]吡啶-2-基)氨基)甲基)-N-羟基苯甲酰胺 (19)。19 被证明是一种泛 HDAC 和 JAK1/2 双抑制剂,对 MDA-MB-231 和 RPMI-8226 两种癌细胞株具有很高的细胞毒性,IC50 值在亚摩尔范围内。对接模拟显示,19 与 HDAC 和 JAK 蛋白的活性位点非常吻合。此外,与 SAHA 相比,19 表现出更好的体外代谢稳定性。我们的研究表明,化合物 19 是一种有希望进行进一步临床前研究的候选化合物。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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