ECCO Grant Final Report: Simona Bertoni & Marco Radi
Simona Bertoni, ECCO Grant Awardee
CCR6 blockade as novel therapeutic strategy against inflammatory bowel disease
|
|
Aim of the research
The CCL20/CCR6 axis is recognized as critical in IBD pathogenesis. However, CCR6 blockage has never been tested as therapeutic approach and no small-molecules CCR6 antagonists have been investigated as a potential anti-IBD drug candidates. Starting from our novel CCR6 antagonist (MR120), we aimed at: -designing and synthesizing more potent CCR6 antagonists; -identifying the most efficacious and tolerable anti-chemotactic CCR6 antagonist; -assessing the efficacy of MR120 and of the most promising novel derivative in adoptive transfer colitis (AT).
Methodology
We generated a collection of analogues around the chemotype of the active hit MR120. The compounds preserving lymphocytes viability were tested for their anti-chemotactic action against CCL20-induced cells recruitment. In AT, MR120 1mg/kg, MR452 1mg/kg, or vehicle (C) were administered for 8 weeks; a sham group received only the vehicle. Local and systemic inflammatory responses were assessed. All experiments were authorized and performed according to the guidelines for the Care and Use of Animals (DL26/2014).
Main findings/results of the research
Among thirty-one newly synthesized molecules, fourteen less cytotoxic compounds were selected and tested in the chemotaxis assay at 25M. Most derivatives improved the anti-chemotactic action compared to MR120: MR452, the most efficacious, was tested in vivo. Versus sham, C mice developed a moderate-to-severe colitis and increased colonic injury and thickening; the augmented neutrophil activity was mitigated by MR120 and MR452.
Conclusions and perceived impact of the findings
MR120 and MR452 attenuated the local granulocytes activity suggesting that the interference with the CCL20/CCR6 axis could hinder leukocytes gut homing and mitigate their inflammatory role. Ongoing morphological, immunohistochemical and biochemical studies will help to better characterize the in vivo profile of both molecules.
Plan of publication
One manuscript (Martina et al., 2022) is in press at Eur J Med Chem. Three more publications are being prepared for submission to medicinal chemistry and pharmacological journals.