2. Academic Validation
  3. Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders

Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders

  • Eur J Med Chem. 2020 Apr 15:192:112155. doi: 10.1016/j.ejmech.2020.112155.
Pengfei Xu 1,  Pei Shen 1,  Bin Yu 1,  Xi Xu 1,  Raoling Ge 2,  Xinying Cheng 1,  Qiuyu Chen 1,  Jinlei Bian 3,  Zhiyu Li 4,  JuBo Wang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 2 Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, 650000, China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China. Electronic address: zhiyuli@cpu.edu.cn.
  • 5 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China. Electronic address: wjb912jh@126.com.
PMID: 32120325 DOI: 10.1016/j.ejmech.2020.112155
Abstract

The Janus kinases or JAKs are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of autoimmune diseases and myeloproliferative disorders. JAKs are activated upon ligand induced receptor homo- or heterodimerization, which results in the immediate phosphorylation of tyrosine residues and the phosphotyrosines then serve as docking sites for cytoplasmic signal transducer and activator of transcription (STAT) proteins which become phosphorylated by the JAKs upon recruitment to the receptor complex. The phosphorylated STAT proteins dimerize and travel to the cellular nucleus, where they act as transcription factors. Interfering in the JAK-STAT pathway has yielded the only approved small molecule kinase inhibitors for immunological indications. Numerous medicinal chemistry studies are currently aimed at the design of novel and potent inhibitors for JAKs. Additionally, whether the second-generation inhibitors which possessed selectivity for JAKs are more efficient are under research. This Perspective summarizes the progress in the discovery and development of JAKs inhibitors, including the potential binding site and approaches for identifying small-molecule inhibitors, as well as future therapeutic perspectives in autoimmune diseases and myeloproliferative disorders are also put forward in order to provide reference and rational for the drug discovery of novel and potent JAKs inhibitors.

Keywords

Autoimmune diseases; JAKs inhibitors; Medicinal chemistry; Rheumatoid arthritis (RA); SAR.

Figures