Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

Abstract

Cytokines, many of which signal through the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway, play a central role in the pathogenesis of inflammatory and autoimmune diseases. Currently three JAK inhibitors have been approved for clinical use in USA and/or Europe: tofacitinib for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, baricitinib for rheumatoid arthritis, and ruxolitinib for myeloproliferative neoplasms. The clinical JAK inhibitors target multiple JAKs at high potency and current research has focused on more selective JAK inhibitors, almost a dozen of which currently are being evaluated in clinical trials. In this narrative review, we summarize the status of the pan-JAK and selective JAK inhibitors approved or in clinical trials, and discuss the rationale for selective targeting of JAKs in inflammatory and autoimmune diseases.

Fig. 1

Schematic presentation of the JAK–STAT (JAK1/JAK3–STAT5) pathway. The panel on the left presents the inhibition mechanism of an ATP-competitive JAK inhibitor. Inhibitor that competes with ATP blocks nucleotide binding and inhibits kinase activity and the phosphorylation of downstream effectors. ATP adenosine triphosphate, JAK Janus kinase, STAT Signal Transducers and Activators of Transcription, γ_c common gamma chain, P phosphate.

Fig. 2

Cytokines (with particular JAKs that mediate the signaling indicated in parentheses) involved in T cell differentiation and function. As the antigen presenting cell engages with the T cell receptor, several cytokines are released to promote the differentiation of various T cell subtypes. Differentiated T cells produce cytokines that contribute to various immune responses and are implicated in inflammatory and autoimmune diseases. AA alopecia areata, AD atopic dermatitis, AS ankylosing spondylitis, CD Crohn’s disease, IFN interferon, IL interleukin, JAK Janus kinase, RA rheumatoid arthritis, SLE systemic lupus erythematosus, TGFβ transforming growth factor-β, Th T helper cell, Treg regulatory T cell, TSLP thymic stromal lymphopoietin, TYK tyrosine kinase, UC ulcerative colitis