JAK/STAT Signaling

JAK–STAT pathway has been used  as a means of intracellular signal transduction in response to cytokines and growth hormones, evolving before the divergence of protostomes from deuterostomes. The canonical signaling cascade is initiated when type I/II cytokines bind to their cognate receptors .Type I/II receptors are composed of distinct chains, which oligomerize upon binding of the cytokine. Oligomerization causes separation of the intracellular subunits of the cytokine receptor, which moves the receptor-associated JAKs apart from each other, relieving constitutive inhibition and resulting in their activation. The JAKs phosphorylate themselves and the intracellular portion of the receptors, which serve as docking sites for STAT transcription factors, which, in turn, are also phosphorylated. When phosphorylated by JAKs, inactive cytosolic STAT monomers undergo a conformational change that allows for the formation of active homodimers,heterodimers, or tetramers. The active STATs can then translocate into the nucleus where they act as transcription factors to regulate gene expression.
Aberrant activation of the JAK/STAT pathway has been reported in a variety of diseases, including inflammatory conditions, hematologic malignancies, and solid tumors. Current Jakinibs act by competitively blocking the adenosine triphosphate-binding site in the JH1 domain through non-covalent interactions. Structural similarities of this binding site to the active domains of several other Tyrosine kinases presented a challenge for the development of a compound that would specifically block JAKs without off-target effects. Furthermore, given the high conservation of the JH1 domain among JAKs, developing a Jakinib that would selectively block one JAK was even more challenging. Despite these difficulties, multiple Jakinibs have been developed with reasonable specificity  and it has become apparent that pan-Jakinibs, with activity against multiple JAKs, are efficacious with an acceptable adverseeffect profile.