Intracellular signaling downstream of type I and type II cytokine receptors is mediated by members of the JAK family and JAK-dependent cytokines are known to play a key role in driving inflammation-dependent pathologies. JAK inhibition represents a rational and clinically validated approach to the treatment of multiple immune-mediated disorders.
Several small molecule inhibitors of members of the JAK family have been approved or are in late-stage clinical trials for the treatment of autoimmune diseases including rheumatoid arthritis and inflammatory bowel diseases1. First-generation inhibitors target members of the JAK family non-selectively by binding their kinase domains, thus inhibiting the downstream activation of transcription factors and resulting pro-inflammatory gene expression. Non-selective JAK inhibitors have gained traction as efficacious treatments for rheumatoid arthritis, but have been associated with dose-limiting toxicity.
1Schwartz, D., Kanno, Y., Villarino, A. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 16, 843–862 (2017). https://doi.org/10.1038/nrd.2017.201