Janus kinases to jakinibs: from basic insights to clinical practice

Abstract

Cytokines are critical mediators of diverse immune and inflammatory diseases. Targeting cytokines and cytokine receptors with biologics has revolutionized the treatment of many of these diseases, but targeting intracellular signalling with Janus kinase (JAK) inhibitors (jakinibs) now represents a major new therapeutic advance. We are still in the first decade since these drugs were approved and there is still much to be learned about the mechanisms of action of these drugs and the practical use of these agents. Herein we will review cytokines that do, and just as importantly, do not signal by JAKs, as well as explain how this relates to both efficacy and side effects in various diseases. We will review new, next-generation selective jakinibs, as well as the prospects and challenges ahead in targeting JAKs.

Keywords: Janus kinases; autoimmunity; cytokines; inflammation; kinase inhibitors; signal transduction.

Published by Oxford University Press on behalf of the British Society for Rheumatology 2019. This work is written by US Government employees and is in the public domain in the US.

Figures

Fig. 1

Schematic of signalling by type I/II cytokines Cytokines that bind the type I/II family of receptors activate receptor-bound JAKs, which catalyse ATP and phosphorylate each other and receptor subunits. Signalling molecules with SH2 domains bind the phosphorylated receptors and are themselves phosphorylated and activated. One such class of molecules is the signal transducer and activator of transcription family of DNA binding proteins, which upon phosphorylation, translocate to the nucleus and regulate gene expression. SH2: src homology 2.

Fig. 2

JAK usage and putative relationship to adverse events Different cytokine receptors bind different combinations of JAKs to activate different programs in cells. First-generation jakinibs broadly impact many cytokines, whereas selective inhibition of JAKs has a more restricted action and in principle is likely to have a narrow spectrum of side effects.