JAK inhibitors

What are JAK inhibitors (Jakinibs)?

JAKs are intracellular proteins that associate with and transduce signals from a number of cytokine and growth factor receptors. There are four JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) that form various homodimers and heterodimers with different pairings being associated with different cell surface receptors. When a specific cytokine or growth factor binds to its cognate receptor causing a conformational change and recruitment of transcription factors, the JAK dimers associated with the specific receptor phosphorylate the recruited transcription factors (e.g., STAT family). These phosphorylated transcription factors dimerize and translocate to the nucleus where they initiate gene transcription resulting in the production of various inflammatory mediators. The following are the JAKs associated with specific cytokine receptors:

  • 1) JAK1.
    • • IL-2, IL-4, IL-7, IL-9, IL-15.
    • • IL-6, IL-10, IL-21, IL-27, IFNα/β, IFNγ.
  • 2) JAK2.
    • • Erythropoietin, thrombopoietin, prolactin, growth hormone, granulocyte-macrophage colony-stimulating factor.
    • • IFNγ, IL-6, IL-12, IL-27 .
  • 3) JAK3 (primarily on hematopoietic cells).
    • • IL-2, IL-4, IL-7, IL-9, IL-15, IL-21.
  • 4) TYK2.
    • • IL-6, IL-10, IL-12, IL-23, IL-27, IFNα/β.

Several small molecules have been developed or are in development that can inhibit one or more of these JAKs. The inhibition of these JAKs will abrogate the effect of specific cytokines/growth factors depending on which JAK is inhibited. This may result in differences in clinical effects and adverse effects (e.g., inhibition of interferons results in herpes infections). This nomenclature assigned to these JAK inhibitors includes “– itinib ” indicating tyrosine inhibition. The following are some of the JAK inhibitors:

  • • FDA-approved:
    • Tofacitinib: JAK3 > JAK1 > JAK2.
    • Baracitinib: JAK1 = JAK2.
  • • In development:
    • Filgotinib: JAK1 selective/preferential.
    • Upadacitinib: JAK1 highly selective (FDA-approved in 2019, Rinvoq 15mg qd).
    • Peficitinib: JAK1/JAK3 > JAK2.
  • • Others

It is important to note that all the JAK inhibitors inhibit all the JAK kinases to some degree even if listed as inhibiting a specific JAK significantly. Although there are differences in immunologic effects in vitro among the various JAK inhibitors, none of them inhibit a cytokine for a full 24 hours due to their short half-life. At therapeutic doses, they all seem to have similar effects and adverse effects.

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