Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors

Several cytokines and growth factors, as well as their downstream signalling pathways, are implicated in the pathogenesis of haematological and immune-mediated diseases. These mediators act through binding to their cognate receptor and activation of one or more of the four Janus family tyrosine kinases (JAKs). Gene knock-out studies together with evidence from patients carrying activating mutant forms of JAKs (eg, JAK2 V617F in myeloproliferative disorders) provided strong rationale for the development of JAK inhibitors. Based on encouraging preclinical data showing the capacity of JAK inhibitors to suppress the signalling from multiple cytokines, an extensive drug development program was set out, with the initial successful introduction of tofacitinib, baricitinib and ruxolitinib in various chronic rheumatic and myeloproliferative diseases, respectively. Importantly, advancements with the design of next-generation, hyper-selective JAK inhibitors hold promise for the better control of inflammation, while reducing the risk for harms, in an expanding spectrum of medical disorders.