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

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

  • Eur J Med Chem. 2022 Aug 29;243:114703. doi: 10.1016/j.ejmech.2022.114703.
Maria Grazia Martina 1,  Carmine Giorgio 1,  Marika Allodi 1,  Simone Palese 1,  Elisabetta Barocelli 1,  Vigilio Ballabeni 1,  Martyna Szpakowska 2,  Andy Chevigné 2,  Jan Piet van Hamburg 3,  Nadine Davelaar 3,  Erik Lubberts 3,  Simona Bertoni 4,  Marco Radi 5
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Degli Alimenti e Del Farmaco, Università Degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy.
  • 2 Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, 4354, Esch-sur-Alzette, Luxembourg.
  • 3 Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
  • 4 Dipartimento di Scienze Degli Alimenti e Del Farmaco, Università Degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy. Electronic address: [email protected].
  • 5 Dipartimento di Scienze Degli Alimenti e Del Farmaco, Università Degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy. Electronic address: [email protected].
PMID: 36067700 DOI: 10.1016/j.ejmech.2022.114703
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.

Keywords

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

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