- Design, synthesis, and structure activity relationship (SAR) studies of novel imidazo[1,2-a] pyridine derivatives as Nek2 inhibitors
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Never in mitosis (NIMA) related kinase 2 (Nek2) is involved in multiple cellular processes such as cell cycle checkpoint regulation, cell division, DNA damage response and cell apoptosis. Nek2 has been reported to be overexpressed in various tumors and correlated with poor prognosis. Herein, a series of imidazo[1,2-a] pyridines Nek2 inhibitors were designed, synthesized, and their biological activities were investigated. Besides, structure activity relationship analysis of these compounds were performed in the MGC-803 cell. The screening results are promising, and compound 28e shows good proliferation inhibitory activity with an IC50 of 38 nM. The results would be helpful to design and develop more effective Nek2 inhibitors for the treatment of gastric cancer.
- Chen, Yunzhong,Du, Yijie,Duan, Yanhong,Gu, Xiaofan,Li, Hongyu,Ma, Mingliang,Ren, Ziwei,Wang, Haili,Wang, Shuting,Xi, Jianbei,Zhang, Xiongwen,Zhu, Tong
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- Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors
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The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms (MPNs). At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21b exhibited high inhibitory activity against JAK2 with an IC50 of 9 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, respectively. Besides, 21b had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound 21b had the potential to be developed as a selective JAK2 inhibitor for further study.
- Diao, Yanyan,Ge, Huan,Li, Honglin,Liu, Dandan,Liu, Wenjun,Xu, Fangling,Xu, Yufang,Zhao, Zhenjiang,Zhu, Lili
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(2022/02/14)
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