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

Xiangyu Ma; Yanyan Diao; Huan Ge; Fangling Xu; Lili Zhu; Zhenjiang Zhao; Honglin Li

doi:10.1016/j.bmcl.2020.127048

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

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127048. doi: 10.1016/j.bmcl.2020.127048. Epub 2020 Feb 18.

Authors

Xiangyu Ma¹, Yanyan Diao¹, Huan Ge¹, Fangling Xu¹, Lili Zhu², Zhenjiang Zhao³, Honglin Li⁴

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
² Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: zhulfl@ecust.edu.cn.
³ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: zhjzhao@ecust.edu.cn.
⁴ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: hlli@ecust.edu.cn.

PMID: 32122740
DOI: 10.1016/j.bmcl.2020.127048

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.

Keywords: JAK2; SAR; SBDD; Selectivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / chemical synthesis
Aminopyridines / chemistry
Aminopyridines / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Aminopyridines
Protein Kinase Inhibitors
JAK2 protein, human
Janus Kinase 2
alpha-aminopyridine