文献类型：期刊文献

英文题名：Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

作者：Liu, Dandan[1];Ge, Huan[1];Xu, Fangling[1];Xu, Yufang[1];Liu, Wenjun[2];Li, Honglin[1,2];Zhu, Lili[1];Diao, Yanyan[1];Zhao, Zhenjiang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Jiangzhong Pharmaceut Co Ltd, Res & Dev Dept, Nanchang 330096, Jiangxi, Peoples R China

年份：2022

卷号：33

期号：6

起止页码：2969

外文期刊名：CHINESE CHEMICAL LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000800344000028)】；

基金：The research is supported in part by the National Key Research and Development Program (No. 2016YFA0502304), the National Natural Science Foundation of China (No. 81825020), the Shanghai Committee of Science and Technology (No. 20S11901000), the Fundamental Research Funds for the Central Universities. Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and the National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：JAK2; Selectivity; Inhibitors; Cancer; Structure-activity relationships

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. (C) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.