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

Abstract：

: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 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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Ma X,Diao Y,Ge H,Xu F,Zhu L,Zhao Z,Li H

doi

10.1016/j.bmcl.2020.127048

subject

Has Abstract

pub_date

2020-04-15 00:00:00

pages

127048

issue

8

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30122-0

journal_volume

30

pub_type

杂志文章

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