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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number114703
JournalEuropean Journal of Medicinal Chemistry
Volume243
DOIs
Publication statusPublished - 5 Dec 2022

Keywords

  • CCL20/CCR6
  • Chemotaxis
  • IBDs
  • Peritonitis
  • Small-molecules
  • TNBS-induced colitis

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