Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases

• DOI: 10.1016/j.ejmech.2022.114703
• Publication Date: 2022-08-29T06:17:30Z
• Authors: Maria Grazia Martina; Carmine Giorgio; Marika Allodi; Simone Palese; Elisabetta Barocelli; Vigilio Ballabeni; Martyna Szpakowska; Andy Chevigné; Jan Piet van Hamburg; Nadine Davelaar; Erik Lubberts; Simona Bertoni; Marco Radi
• Keywords: CCL20

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.