C-C chemokine receptor 9 (CCR9) is the homing receptor for C-C motif chemokine ligand 25 (CCL25), and contributes to the maintenance of mucosal immunity and pathogenesis of inflammatory bowel disease (IBD) through the recruitment of T cells into the gut mucosa. Recent reports suggest that the interaction of CCR9 and CCL25 in the large intestine correlate with disease severity of colonic IBD. MLN3126 is an orally available small molecular compound with potent and selective CCR9 antagonist activity. MLN3126 inhibited CCL25-induced calcium mobilization in human CCR9 transfected cells and CCL25-induced chemotaxis of mouse primary thymocytes in a dose-dependent manner. The potential effect of MLN3126 in an activated T cell transfer mouse colitis model was compared with that of an anti-tumor necrosis factor (TNF)-α antibody. CCL25 protein was detected in the colon of mucosal epithelial cells and CCR9⁺ CD4⁺ T cells were observed in the lamina propria of the colon of mice with colitis. Dietary administration of MLN3126 to the mice maintained sufficient concentration of the compound in the plasma and dose-dependently inhibited progression of colitis compared to the vehicle control group. Anti-TNF-α antibody, a surrogate for a standard of care for IBD treatment, was also efficacious in the colitis model. These results suggest that MLN3126 would be a promising orally available CCR9 antagonist to treat colonic IBD.

CC趋化因子受体9（CCR9）是CC基序趋化因子配体25（CCL25）的归巢受体，通过将T细胞募集到肠道粘膜中，有助于维持粘膜免疫力和炎症性肠病（IBD）的发病机理。最近的报道表明，CCR9和CCL25在大肠中的相互作用与结肠IBD的疾病严重程度相关。MLN3126是具有有效和选择性CCR9拮抗剂活性的口服小分子化合物。MLN3126以剂量依赖性方式抑制人CCR9转染的细胞中CCL25诱导的钙动员和CCL25诱导的小鼠原代胸腺细胞的趋化性。将MLN3126在激活的T细胞转移小鼠结肠炎模型中的潜在作用与抗肿瘤坏死因子（TNF）-α抗体的潜在作用进行了比较。在结肠炎小鼠结肠固有层中观察到⁺ CD4 ⁺ T细胞。与媒介物对照组相比，对小鼠进行饮食日粮投予MLN3126可维持血浆中化合物的足够浓度，并剂量依赖性地抑制结肠炎的进展。抗TNF-α抗体是IBD治疗的标准护理替代品，在结肠炎模型中也有效。这些结果表明，MLN3126将成为治疗结肠IBD的有希望的口服CCR9拮抗剂。