Selective JAK1 inhibitors for the treatment of inflammatory bowel disease

Janus kinase (JAK) inhibitors, also known as jakinibs, are third-generation oral small molecules that have expanded the therapeutic options for the management of chronic inflammatory diseases, including inflammatory bowel disease (IBD). Tofacitinib, a pan-JAK inhibitor, has spearheaded the new JAK class for IBD treatment. Unfortunately, serious adverse effects, including cardiovascular complications such as pulmonary embolism and venous thromboembolism or even death from any cause, have been reported for tofacitinib. However, it is anticipated that next-generation selective JAK inhibitors may limit the development of serious adverse events, leading to a safer treatment course with these novel targeted therapies. Nevertheless, although this drug class was recently introduced, following the launch of second-generation biologics in the late 1990s, it is breaking new ground and has been shown to efficiently modulate complex cytokine-driven inflammation in both preclin-ical models and human studies. Herein, we review the clinical opportunities for targeting JAK1 signaling in the pathophysiology of IBD, the biology and chemistry underpinning these target-selective compounds, and their mechanisms of actions. We also discuss the potential for these inhibitors in efforts to balance their benefits and harms.(c) 2023 Published by Elsevier Inc.

Automated summary

JAK inhibitors are a new class of oral small molecules that provide therapeutic options for chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, current JAK inhibitors may have serious adverse effects, and next-generation selective JAK inhibitors are expected to reduce these complications. Despite these concerns, JAK inhibitors have shown promise in modulating cytokine-driven inflammation and offer potential benefits in the treatment of IBD.