Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

Wanqi Wang; Yanyan Diao; Wenjie Li; Yating Luo; Tingyuan Yang; Yuyu Zhao; TianTian Qi; Fangling Xu; Xiangyu Ma; Huan Ge; Yingfan Liang; Zhenjiang Zhao; Xin Liang; Rui Wang; Lili Zhu; Honglin Li; Yufang Xu

doi:10.1016/j.bmcl.2019.04.011

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1507-1513. doi: 10.1016/j.bmcl.2019.04.011. Epub 2019 Apr 6.

Authors

Wanqi Wang¹, Yanyan Diao¹, Wenjie Li¹, Yating Luo¹, Tingyuan Yang¹, Yuyu Zhao¹, TianTian Qi¹, Fangling Xu¹, Xiangyu Ma¹, Huan Ge¹, Yingfan Liang¹, Zhenjiang Zhao¹, Xin Liang¹, Rui Wang¹, Lili Zhu², Honglin Li³, Yufang Xu⁴

Affiliations

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

PMID: 30981578
DOI: 10.1016/j.bmcl.2019.04.011

Abstract

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC₅₀ = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC₅₀ = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.

Keywords: Crizotinib; JAK2; Molecular docking; Rheumatoid arthritis.

Publication types

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

MeSH terms

Animals
Humans
Janus Kinase 2 / antagonists & inhibitors*
Molecular Structure
Pyrimidines / pharmacology
Pyrimidines / therapeutic use*
Rats
Structure-Activity Relationship

Substances

Pyrimidines
Janus Kinase 2