Development of JAK inhibitors for the treatment of immune-mediated diseases: kinase-targeted inhibitors and pseudokinase-targeted inhibitors.

JAKs are a family of intracellular tyrosine kinases consisting of four members, JAK1, JAK2, JAK3, and TYK2. They are key components of the JAK-STAT pathway that transmit signals of many cytokines involved in the pathogenesis of numerous immune-mediated diseases and have been major molecular targets in developing new drugs for the treatment of such diseases. Some small-molecule inhibitors of JAKs have been approved by the FDA for rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. Now, newer JAK inhibitors with isoform-selectivity among the four different JAKs are being developed, with the aim of improving clinical outcomes compared with earlier developed drugs with pan-JAK inhibition. Most of these selective inhibitors target the kinase domains of JAKs, functioning through the traditional inhibition mode of kinases; but recently those that target their pseudokinase domains, allosterically inhibiting the enzymes, have been under development. In this review, key characteristics, efficacy, and safety of FDA-approved and representative drugs in late stages of development are briefly described in order to provide clinical implications with respect to JAK inhibitor selectivity and future development perspectives. The recent development of pseudokinase-targeted inhibitors of JAKs is also included.