Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists

Abstract

The inflammatory Bowel diseases (IBDs) are a chronic, relapsing inflammatory diseases of the gastrointestinal tract with heterogeneous behavior and prognosis. The introduction of biological therapies including anti-TNF, anti-IL-12/23, and anti-integrins, has revolutionized the treatment of IBD, but these drugs are not universally effective. Due to the complex molecular structures of biologics, they are uniformly immunogenic. New discoveries concerning the underlying mechanisms involved in the pathogenesis of IBD have allowed for progress in the development of new treatment options. The advantage of small molecules (SMs) over biological therapies includes their lack of immunogenicity, short half-life, oral administration, and low manufacturing cost. Among these, the Janus Kinases (JAKs) inhibition has emerged as a novel strategy to modulate downstream cytokine signaling during immune-mediated diseases. These drugs target various cytokine signaling pathways that participate in the pathogenesis of IBD. Tofacitinib, a JAK inhibitor targeting predominantly JAK1 and JAK3, has been approved for the treatment of ulcerative colitis (UC), and there are other specific JAK inhibitors under development that may be effective in Crohn’s. Similarly, the traffic of lymphocytes can now be targeted by another SM. Sphingosine-1-phosphate receptor (S1PR) agonism is a novel strategy that acts, in part, by interfering with lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. S1PR agonists are being studied in IBD and other immune-mediated disorders. This review will focus on SM drugs approved and under development, including JAK inhibitors (tofacitinib, filgotinib, upadacitinib, peficitinib) and S1PR agonists (KRP-203, fingolimod, ozanimod, etrasimod, amiselimod), and their mechanism of action.

Fingolimod inhibits multiple stages of the HIV-1 life cycle

“…The compound is clinically approved for treatment of Multiple Sclerosis [ 23 , 24 ] and is well-tolerated when taken orally on a daily basis [ 25 , 26 ]. FTY720 has activity at four of the five S1P receptors (S1PR1, 3, 4 and 5) and has been shown to cause downregulation of S1PR1 in lymphocytes and act as a modulator of S1P signaling, effecting changes in chemotaxis, proliferation, and cell cycle state of lymphocytes and other cells [ 15 , 21 , 27 – 29 ]. In the case of S1PR1, FTY720 binds to this receptor when phosphorylated and causes its internalization and loss of signaling [ 27 ].…”

Erfolgreiche Therapie einer Alopecia areata partim universalis mit Tofacitinib

“…Im Gegensatz zu der oralen Anwendung zeigte sich die Lokaltherapie mit JAKis nicht vergleichsweise erfolgreich [11]. Die JAKis werden i. d. R. gut vertragen und sind mit milden Nebenwirkungen verbunden (Infektionen, Dyslipidämie und Blutbild-Veränderungen) [11,12]. Schwere Nebenwirkungen der JAKis wie thromboembolische Episoden sind in Studien mit Rheuma-Patienten beschrieben, diese könnten jedoch auf die Grunderkrankung selbst und ihre Komorbiditäten zurückzuführen sein [13].…”

Conventional and Future Therapies for Crohn's Disease

“…The binding of STAT to JAK results in its dimerization and nuclear translocation where it stimulates transcription activation and gene expression of pro-inflammatory molecules. JAK inhibitors mitigate this cascade resulting in reduced mucosal inflammation in CD [52].…”