Design, Synthesis and Biological Evaluation of Arylpyridin-2-yl Guanidine Derivatives and Cyclic Mimetics as Novel MSK1 Inhibitors. An Application in an Asthma Model.

Fiche publication

Date publication

janvier 2021

Journal

Molecules (Basel, Switzerland)

Auteurs

Membres identifiés du Cancéropôle Est :
Dr VILLA Pascal

Tous les auteurs :
Bollenbach M, Nemska S, Wagner P, Camelin G, Daubeuf F, Obrecht A, Villa P, Rognan D, Bihel F, Bourguignon JJ, Schmitt M, Frossard N

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33450992

Résumé

Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound , IC~18 µM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC~2 µM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma.