化学
克里唑蒂尼
磷酸化
选择性
药理学
激酶
结构-活动关系
立体化学
生物化学
体外
内科学
生物
医学
胸腔积液
恶性胸腔积液
催化作用
作者
Dandan Liu,Huan Ge,Fangling Xu,Yufang Xu,Wenjun Liu,Honglin Li,Lili Zhu,Yanyan Diao,Zhenjiang Zhao
标识
DOI:10.1016/j.cclet.2021.12.099
摘要
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 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.
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