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

作者：Zhengshui Xu, Changchun Ye, Xingjie Wang, Ranran Kong, Zilu Chen, Jing Shi, Xin Chen, Shiyuan Liu · 发表于：Journal of Enzyme Inhibition and Medicinal Chemistry · 年份：2024 · DOI：10.1080/14756366.2024.2409771 · 被引用次数：9 · 研究领域：Histone Deacetylase Inhibitors Research、Peptidase Inhibition and Analysis、Protein Degradation and Inhibitors

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.