TY - JOUR
T1 - Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases
AU - Martina, Maria Grazia
AU - Giorgio, Carmine
AU - Allodi, Marika
AU - Palese, Simone
AU - Barocelli, Elisabetta
AU - Ballabeni, Vigilio
AU - Szpakowska, Martyna
AU - Chevigné, Andy
AU - Piet van Hamburg, Jan
AU - Davelaar, Nadine
AU - Lubberts, Erik
AU - Bertoni, Simona
AU - Radi, Marco
N1 - Funding Information:
This work was supported by the University of Parma and by the European Crohn's and Colitis Organisation (to S.B. and M.R.), the Luxembourg Institute of Health (LIH) and Luxembourg National Research Fund (INTER/ FNRS / 20/15084569 to A.C. and M.S.) and FNRS Télévie ( 7.8508.22 , 7.8504.20 and 7.4593.19 to A.C. and M.S). M.S, A.C., and M.R. are members of the COST Action CA 18133 “European Research Network on Signal Transduction─ERNEST”. Prof. Federica Vacondio is also acknowledged for helpful discussion and interactions.
Publisher Copyright:
© 2022 Elsevier Masson SAS
PY - 2022/12/5
Y1 - 2022/12/5
N2 - 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.
AB - 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.
KW - CCL20/CCR6
KW - Chemotaxis
KW - IBDs
KW - Peritonitis
KW - Small-molecules
KW - TNBS-induced colitis
UR - https://www.scopus.com/pages/publications/85137293920
UR - https://pubmed.ncbi.nlm.nih.gov/36067700
U2 - 10.1016/j.ejmech.2022.114703
DO - 10.1016/j.ejmech.2022.114703
M3 - Article
C2 - 36067700
AN - SCOPUS:85137293920
SN - 0223-5234
VL - 243
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114703
ER -