Dipartimento di Scienze Degli Alimenti e Del Farmaco, Università Degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy.
Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-sur-Alzette, Luxembourg.
Eur J Med Chem. 2022 Dec 5;243:114703. doi: 10.1016/j.ejmech.2022.114703. Epub 2022 Aug 29.
The CCL20/CCR6 axis is implicated in the migration of CCR6+ immune cells towards CCL20, its sole ligand, whose expression is increased during inflammatory processes and is known to play a pivotal role in triggering different autoimmune-mediated inflammatory diseases. Herein, we report a drug discovery effort focused on the development of a new pharmacological approach for the treatment of inflammatory bowel diseases (IBDs) based on small-molecule CCR6 antagonists. The most promising compound 1b was identified by combining in silico studies, sustainable chemistry and in vitro functional/targeted assays, and its efficacy was finally validated in a classic murine model of colitis (TNBS-induced) and in a model of peritonitis (zymosan-induced). These data provide the proof of principle that a pharmacological modulation of the CCL20/CCR6 axis may indeed represent the first step for the development of an orally bioavailable drug candidate for the treatment of IBD and, potentially, other diseases regulated by the CCL20/CCR6 axis.
CCL20/CCR6 轴参与 CCR6+免疫细胞向其唯一配体 CCL20 的迁移，其表达在炎症过程中增加，已知在触发不同的自身免疫介导的炎症性疾病中发挥关键作用。在此，我们报告了一项药物发现工作，该工作侧重于基于小分子 CCR6 拮抗剂开发治疗炎症性肠病 (IBD) 的新的药理学方法。通过将计算机研究、可持续化学和体外功能/靶向测定相结合，确定了最有前途的化合物 1b，并最终在经典的结肠炎 (TNBS 诱导) 小鼠模型和腹膜炎 (酵母聚糖诱导) 模型中验证了其疗效。这些数据提供了一个原理上的证明，即对 CCL20/CCR6 轴的药理学调节确实可能代表开发用于治疗 IBD 的口服生物利用候选药物的第一步，并且可能代表治疗由 CCL20/CCR6 轴调节的其他疾病的第一步。
