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

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.
Wanqi Wang 1,  Yanyan Diao 1,  Wenjie Li 1,  Yating Luo 1,  Tingyuan Yang 1,  Yuyu Zhao 1,  TianTian Qi 1,  Fangling Xu 1,  Xiangyu Ma 1,  Huan Ge 1,  Yingfan Liang 1,  Zhenjiang Zhao 1,  Xin Liang 1,  Rui Wang 1,  Lili Zhu 2,  Honglin Li 3,  Yufang Xu 4
Affiliations

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.

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