JAK–STAT pathway targeting for the treatment of inflammatory bowel disease. Salas et al. 2020. Nature Reviews Gastroenterology & Hepatology.

Inflammatory bowel disease (IBD) is generally characterized by a chronic inflammation of the gastrointestinal tract. A group of molecules called cytokines are involved in this process, as well as in the sustainment of the intestinal homeostasis. Many cytokines exert their action through signalling proteins called Janus kinases (JAKs); as a consequence, JAK kinases have the potential to affect multiple pro-inflammatory pathways involved in IBD. Accordingly, several inhibitors of JAKs are being developed and one of them, tofacitinib, is already approved for ulcerative colitis. 

In this review published by researchers from IDIBAPS, one of the partners of the New Deal project, you will find insights about the role of JAK signalling in intestinal homeostasis and IBD. The publication discusses the future landscape of the treatments that target this pathway and the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD.

 

Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease. Leonard et al. 2020. J. Med. Chem. 63, 6, 2915-2929.

JAK kinases are considered promising molecular targets to treat IBD. These proteins are involved in the activation of immune cells that trigger an excessive intestinal inflammation in IBD patients. Currently, there is only one approved drug, tofacitinib, that exploits this target to treat IBD. However, this treatment shows systemic adverse effects due to JAK kinases being part of many inflammatory responses in the body. An alternative could be to limit the JAK inhibition to the gastrointestinal tract and maximise it on the intestinal tissue to avoid systemic adverse effects. 

In this article, researchers have focused on developing a JAK inhibitor with a cellular potency similar to tofacitinib’s but with physicochemical properties that allow to limit the drug exposure to the intestinal tract. Researchers have identified low permeability JAK inhibitors that have displayed high colonic and low systemic exposure in mice. These specific inhibitors may be a feasible approach for the next generation of biologic IBD drugs.