Basic Mechanisms of JAK Inhibition

Over recent decades, treatment options for inflammatory diseases such as rheumatoid arthritis (RA) have increased dramatically. These range from orally available steroids and conventional synthetic disease modifying drugs (csDMARDs) to parenteral biological therapies (bDMARDs). Most recently, with advances in our understanding of cell signalling pathways, we can target small molecules associated with intracellular signal transduction.1 These orally available drugs form a new category of treatment known as targeted synthetic DMARDs (tsDMARDs).2 The first drug class within this category to gain marketing authorisations are the Janus Kinase inhibitors (JAK inhibitors or jakinibs).3 By inhibiting Janus Kinases, these drugs inhibit signalling through a variety of cytokine and haematopoietic growth factor receptors.4 There are four members of the JAK family, and all are receptor-associated tyrosine kinases (JAK1, JAK2, JAK3 and TYK2).4 Tyrosine kinases are phosphotransferase enzymes which transphosphorylate tyrosine residues on other proteins. This process can trigger (usually) or hinder (less commonly) the activity of the target protein, often as part of an enzymatic cascade.5,6 All JAKs work in a similar manner, usually in association with type I and II cytokine receptors, which are intrinsic elements of immune responses.7,8 Consequently, inhibiting these enzymes has great potential for controlling unwanted or overactive immune pathways.9 It is important to understand both the role of cytokines in regulating immune function and the JAK-STAT (signal transducer and activators of transcription) pathways in order to fully appreciate the true value of JAK inhibition, especially in relation to its role in diseases such as RA.5,8 Cytokines form a large family of (mostly) soluble mediators, which are responsible for controlling a wide range of bodily processes, from growth to haematopoiesis. They play an important role in both innate and adaptive arms of the immune response.9,10 Unsurprisingly, an imbalance of their activity is associated with a number of different autoimmune diseases and malignancies.11,12 Anti-inflammatory agents such as glucocorticoids, as well as csDMARDs, can impair cytokine secretion and downstream activities, but long-term use and off-target effects result in unwanted side effects, such as osteopenia and liver toxicity.13,14 Some bDMARDs (TNF inhibitors, IL-6 receptor blockers) target pro-inflammatory cytokines themselves, with significant benefit. These bDMARDs have contributed to the revolution in the management of autoimmunity but they are expensive, require parenteral administration, as well as co-prescription with methotrexate (MTX) to achieve optimal outcomes.15–17 Many patients with RA prefer oral drug therapy, triggering an unmet need for potent oral medications.17 Using synthetic, orally available drugs to target intracellular signalling pathways has the potential to meet this need, potentially matching biological efficacy within a pill.2–6 The JAK-STAT pathways provided rational targets due to their involvement in cytokine signalling, including cytokines thought to be active in RA, such as interleukins, interferons and growth factors.5,8