文献类型：期刊文献

英文题名：Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

作者：Ma, Xiangyu[1];Diao, Yanyan[1];Ge, Huan[1];Xu, Fangling[1];Zhu, Lili[1];Zhao, Zhenjiang[1];Li, Honglin[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China

年份：2020

卷号：30

期号：8

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000519194300010)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304), the National Natural Science Foundation of China (grant 81825020), the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (No. 2018ZX09711002), the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No. U1501501. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：JAK2; Selectivity; SBDD; SAR

摘要：Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular non-receptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC50 of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structureactivity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.