Copyright ©The Author(s) 2023.
World J Gastroenterol. Jan 7, 2023; 29(1): 110-125
Published online Jan 7, 2023. doi: 10.3748/wjg.v29.i1.110
Table 1 Sphingosine-1-phosphate modulators and mechanism of action in inflammatory bowel disease
S1P modulator
Mechanism of action in IBD
Developmental phase
Amiselimod (MT-1303)Modulator of the S1P1 receptor→ S1P1; Internalization into lymphocytes→↓migration to the periphery; ↓Infiltration of pro-inflammatory Th1/Th17 cells into the colon; ↑Tregs in mesenteric lymph nodesPhase IIa[73-75]
Fingolimod (FTY720)Specific inhibitor of S1PR1; Interferes with S1P signaling→↓lymphocyte entry into lymph nodes; ↑CD4+CD25+FOXP3+ T cells, ↑CD25, FOXP3 expression, Treg activity; ↑Immunosuppressive cytokines IL-10 and TGF-β and CTLA-4→↑Treg-mediated immunomodulation; ↓Pro-inflammatory signaling (IL-12p70, Th1 cytokines); ↓Pro-inflammatory signals on dendritic cells→↑activity of CD4+CD25+ TregsPreclinical studies, not tested in humans[76-83]
Etrasimod (APD-334)Agonist of S1P1, partial agonist of S1P4/S1P5; Lymphopenia, ↓mucosal thickness, immune cell infiltration, expression of T-cell and monocyte markers; ↓Pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17A, ↑anti-inflammatory IL-10Phase II/IIINCT03996369, NCT03945188, NCT03950232, NCT04173273[84-86]
Ozanimod (RPC-1063)Selective S1P1 and S1P5 receptor agonist; ↓T cell migration→↓peripheral lymphocytes↑S1P1 receptor internalization and degradation; ↓Circulating B and CCR7+ T lymphocytes→↓inflammation; ↓Mononuclear cell infiltrate and mucosal thicknessPhase II/IIINCT03440385, NCT03464097, NCT03467958, NCT03440372[87-92]
KRP-203Modulator of S1P1 receptor, partial agonist of S1PR3 receptor; Lymphopenia, ↑homing of lymphocytes to peripheral lymph nodes; ↓Infiltration of inflammatory cells in the lamina propria of the intestine; ↓CD4+ T and B220+ B cells in peripheral blood and in the lamina propria of the colon; ↓Peripheral naive and central memory CD4+ and CD8+ T cells and B cells; ↑Lymphocytes in mesenteric lymph nodes and spleen; ↓Pro-inflammatory cytokines IFN-γ, TNF-α, and IL-12 in the lamina propria of the colonPhase II[93-96]
LCL351SphK1 inhibitor→↓S1P production; ↓Neutrophil infiltration into sites of inflammation, ↓inflammatory marker TNF-α; Altered S1P levels and ↓neutrophil chemoattractants CXCL1 and CXCL2→↓leukocyte recruitment to sites of inflammationPreclinical studies[43,97]
ABC747080 and ABC294640Inhibitors of SphKs→↓S1P formation, SphK activity; ↓TNF-α-induced activation of NF-Κβ; ↓Effects of TNF-α on leukocyte recruitment and TNF-α- mediated increase in adhesion protein expression levels; ↓Pro-inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-6) in colon tissuePreclinical studies[98]
DOP and THIS1P lyase inhibitors; Peripheral lymphopenia, ↓CD4+ and CD8+ T cells; ↓Pro-inflammatory cytokines, including TNF-α, IL-6, IL-12, IFN-γ and IL-17; ↓S1PR1 expression on T lymphocytes; Depletion of late immature T cells (CD4+CD8+ double positive) and mature CD4+CD8- and CD4-CD8+ single positive cellsPreclinical studies[99,100]
W-061S1P receptor agonist; ↓Lymphocyte migration to the spleen and lamina propria, pro-inflammatory Th1 and Th17 cells in the lamina propria→ prevention of changes in intestinal mucosal architecturePreclinical studies[101]
SEW2871S1P1 agonist; Mild inflammatory cell infiltration, ↓CD4+ T cells in the lamina propria of the colon; ↓Pro-inflammatory cytokines TNF-α and IFN-γ were significantly reduced in colonic tissues; Improved intestinal barrier function, ↑typical tight junction protein expression and distribution in the intestinal epithelium; ↓Apoptosis of intestinal epithelial cells→ restoration of colon tissue injuryPreclinical studies[102,103]