JAK inhibitor selectivity: new opportunities, better drugs?

Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action. This Review provides an update on developments in Janus kinase inhibitors, including new disease indications and adverse effects. The authors discuss issues surrounding selectivity and efficacy, as well as new routes for administration of Janus kinase inhibitors. Key points: Januse kinase (JAK) inhibitors show equivalent or superior efficacy compared with biologic DMARDs in several autoimmune and inflammatory diseases. The use of JAK inhibitors has been hampered by adverse events, which could be linked to the JAKs that are blocked. Assessment of individual JAK inhibitor selectivity is still a matter of debate, as different assays can yield different results. Selective JAK inhibitors are generally equally effective, but improved, long-term safety has not been fully established. Tissue-targeted JAK inhibitors could circumvent the problem of adverse effects resulting from systemic administration. Alternative strategies for JAK inhibition with small interfering RNAs or metabolite derivatives constitute an exciting area of development. [ABSTRACT FROM AUTHOR]