Working and safety profiles of JAK/STAT signaling inhibitors. Are these small molecules also smart?

The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is an important intracellular route through which many different extracellular soluble molecules, by reaching membrane receptors, can signal the nucleus. The spectrum of soluble molecules that use the JAK/STAT pathway through their corresponding receptors is quite large (almost 50 different molecules), and includes some cytokines involved in the pathogenesis of many immune-mediated diseases. Such diseases, when left untreated, present an evident hyperactivation of JAK/STAT signaling. Therefore, given the pathogenetic role of JAK/STAT, drugs known as JAK inhibitors (JAKi), that target one or more JAKs, have been developed to counteract JAK/STAT signal hyperactivation. As some hematological malignancies present an intrinsic JAK/STAT hyperactivation due to a JAK mutation, some JAKi have also been successfully used in this context. Regulatory agencies for drug administration in different countries have already approved a few JAKi in the setting of either immune-mediated diseases or hematological malignancies. Aim of this review is to describe the physiology of intracellular JAK/STAT pathway signaling and the pathological conditions associated to its dysregulation. Then, the rationale for targeting JAK in rheumatic autoimmune diseases is discussed, along with clinical data from registration studies showing the efficacy of these drugs. Finally, the excellent safety profile of JAKi is discussed in the context of the apparent poor specificity of JAK/STAT pathway signal.