Revisiting Janus kinases as molecular drug targets for rheumatic diseases

Janus kinase (JAK) family members, as upstream regulators, phosphorylate not only themselves but also cytokine receptors and signal transducer and activator of transcription (STAT) proteins in the JAK-STAT signaling pathway. The JAK-STAT pathway is associated with various cellular processes, such as cell proliferation, cell death, and immune responses. Considering that the JAK-STAT pathway is involved in immunity, dysfunctional JAKs can cause autoimmune diseases, including rheumatoid arthritis. Therefore, several inhibitors have been developed to inhibit the function of JAKs in the case of abnormal JAK-STAT signaling. Emerging structural data on JAKs highlight the opportunities to design selective inhibitors that can overcome mutation-driven resistance. Therefore, novel JAK inhibitors need to be developed. In this review, we discuss the principal structural features of JAKs, focusing on the active site. In addition, we summarized the updated JAK inhibitors indicated for rheumatoid arthritis that are available in the pharmaceutical market. The binding modes of JAK inhibitors have also been described. Based on the structural analysis of JAKs and their inhibitors, we propose strategies for developing next-generation JAK inhibitors.