Novel Small Molecules in IBD: Current State and Future Perspectives

Abstract

Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn's disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials.

Keywords: Crohn’s; JAK; inflammatory bowel diseases; small molecular drugs; small molecules; ulcerative colitis.

Figure 1

When cytokines (e.g., INF-γ) activate immune cells such as macrophages, cytokine receptors depend on JAK to activate the transcription factors of the STAT family. STAT promotes pro-inflammatory gene expression, resulting in, e.g., release of IL-23. JAK inhibitors prevent cytokine signaling at the beginning of the intracellular cascade. Created with biorender.com.

Figure 2

Cobitolimod activates as an oligodeoxynucleotide TLR-9 on immune cells and thereby releases anti-inflammatory cytokines (e.g., IL-10). Created with biorender.com.

Figure 3

Obefazimod binds to and stabilizes cap-binding complex (CBC), leading to enhanced splicing of the miR-124 precursor, and thus, increased production of miR-124. This results in less pro-inflammatory signaling (e.g., via IL-6 and STAT3). Created with biorender.com.