Basic Mechanisms of JAK Inhibition

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. The importance of these pathways in health and disease has been demonstrated through multiple studies involving knockout mice and mutagenized cell lines.20-22 Of more relevance, certain types of human primary immunodeficiencies such as severe combined immunodeficiency (SCID), are caused by non-redundant mutations related to these pathways.23,24 In contrast, overexpression of these pathways is associated with both autoimmune disease and malignancy.25-28 Consequently, their blockade provides a means to block, simultaneously, the actions of multiple key cytokines associated with autoimmunity.1 SPECIFICITY VS SELECTIVITY Each JAK enzyme contains an ATP binding pocket which is critical to their function. [...]as the intracellular concentration of the drug increases it is likely to affect ATP binding to these other JAK family members, with loss of selectivity (Figure 2).33,34 Rather than lock and key, this can be thought of as fingers in gloves, and it is unlikely that a jakinib can be developed that is completely specific for a single JAK.35 Intracellular concentration depends not only on dosing, but on factors specific to each patient, such as age, weight, liver and kidney function, other medications, etc.It should also be stressed that selectivity is usually deduced from reductionist laboratory enzymatic or cellular assays, which may or may not reflect the in vivo situation.12 Early phase (phase 1, 2) clinical trials aim to identify the optimal drug dose, at a population level, in terms of achieving optimal selectivity.36 However, it is real life experience, in a typical patient population, when rheumatologists need to judge the selectivity of a particular therapeutic. Only JAK2 acts as a homodimer,