Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders

Pharmacol Res. 2022 Sep;183:106362. doi: 10.1016/j.phrs.2022.106362. Epub 2022 Jul 22.

Abstract

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

Keywords: Abrocitinib (PubChem CID: 78323835); Atopic dermatitis; Baricitinib (PubChem CID: 44205240); Belumosudil (PubChem CID: 11950170); Fedratinib (PubChem CID: 16722836); Fostamatinib (PubChem CID: 11671467); Leukemia; Myelofibrosis; Nintedanib (PubChem CID: 135423438); Pacritinib (PubChem CID: 46216796); Polycythemia vera; Rheumatoid arthritis; Ruxolitinib (PubChem CID: 25126798); STAT; Tofacitinib (PubChem CID: 9926791); Upadacitinib (PubChem CID: 58557659).

Publication types

  • Review

MeSH terms

  • Arthritis, Rheumatoid* / drug therapy
  • COVID-19*
  • Humans
  • Janus Kinase 1
  • Janus Kinase 2 / metabolism
  • Janus Kinase Inhibitors* / pharmacology
  • Janus Kinase Inhibitors* / therapeutic use
  • Janus Kinases / metabolism
  • Polycythemia Vera*
  • Primary Myelofibrosis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • Janus Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinases