Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor 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 myelofibroisis (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. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.

User Login


Database


PTID

Contact us


Honglin Li's Lab
Shanghai Key Laboratory of New Drug Design
School of Pharmacy
East China University of Sci. & Tech.
Room 527, Building 18, 130 Meilong Road,
Shanghai, 200237, P. R. China
Tel: (86) 21 6425 0213
Prof. Honglin Li
hlli@ecust.edu.cn

Copyright © 2020 Prof. HongLin Li's Group, School of Pharmacy, East China University of Science & Technology · All Right Reserved.
沪ICP备19004698号-1 |  沪公网安备31011302004713号