Selective JAK1 inhibitors for the treatment of inflammatory bowel disease

Pharmacol Ther. 2023 May:245:108402. doi: 10.1016/j.pharmthera.2023.108402. Epub 2023 Mar 31.

Abstract

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 preclinical 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.

Keywords: Crohn's disease; Janus kinase 1; Signal transducers and activators of transcription; Small molecules; Therapy; Ulcerative colitis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines
  • Humans
  • Inflammation / drug therapy
  • Inflammatory Bowel Diseases* / drug therapy
  • Janus Kinase 1
  • Janus Kinase Inhibitors* / adverse effects

Substances

  • Janus Kinase Inhibitors
  • Cytokines
  • JAK1 protein, human
  • Janus Kinase 1