SPH7854, a gut-limited RORγt antagonist, ameliorates TNBS-induced experimental colitis in rat

• Published in: International immunopharmacology Vol. 140; p. 112884
• Main Authors: Xiang, Zhijun, Zhang, Bingbin, Cao, Shuangyi, Cao, Long, Li, Lingwen, huang, Dehua, Li, Qian, Chen, Yuxiang, Gong, Xuelian, Zhang, Xiaohong, Li, Ruizhi, Wu, Jinmiao, Peng, Yayuan, Huo, Guoyong, Xu, Lixia, Zhang, Zhihui, Li, Di, Xia, Guangxin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.10.2024
• Subjects: Colitis; Gut-limited; IBD; RORγt; Th17; Treg; IBD; Colitis; Th17; Gut-limited; Treg; RORγt
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112884

[Display omitted] •The imbalance of Th17 cells/Treg cells in mucosa of gastrointestinal tract often results in the recruitment and activation of neutrophil and macrophage, as well as the release of pro-inflammatory cytokine or mediator, contributing the pathogenesis of IBD.•Modulation of the ratio of Th17 cells/Treg cells through blocking the activity of RORγt is a potential strategy for IBD treatment. However, the adverse sides of systemic blockade of RORγt hampered the clinical development of RORγt antagonist.•Gut-restricted drugs can achieve high local concentrations at the site of action while minimizing systemic exposure, lowering the safe risks arising from on- and off-target activity elsewhere in the body.•SPH7854, a gut-restricted RORγt selective antagonist, significantly ameliorated TNBS-induced murine colitis possibly through decreasing the Th17/Treg cell ratio and subsequently reducing the recruitment and activation of neutrophils and macrophages as well as the release of pro-inflammatory cytokines or mediators in mucosa of colon. Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.