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 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 IC ₅₀ 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020. Published by Elsevier Ltd.)