Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors.
Fiche publication
Date publication
décembre 2021
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
Tous les auteurs :
Tahtouh T, Durieu E, Villiers B, Bruyère C, Nguyen TL, Fant X, Ahn KH, Khurana L, Deau E, Lindberg MF, Sévère E, Miege F, Roche D, Limanton E, L'Helgoual'ch JM, Burgy G, Guiheneuf S, Herault Y, Kendall DA, Carreaux F, Bazureau JP, Meijer L
Lien Pubmed
Résumé
The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.
Référence
J Med Chem. 2021 Dec 20;: