- Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors
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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.
- Tahtouh, Tania,Durieu, Emilie,Villiers, Beno?t,Bruyère, Céline,Nguyen, Thu Lan,Fant, Xavier,Ahn, Kwang H.,Khurana, Leepakshi,Deau, Emmanuel,Lindberg, Mattias F.,Sévère, Elodie,Miege, Frédéric,Roche, Didier,Limanton, Emmanuelle,L’Helgoual’ch, Jean-Martial,Burgy, Guillaume,Guiheneuf, Solène,Herault, Yann,Kendall, Debra A.,Carreaux, Fran?ois,Bazureau, Jean-Pierre,Meijer, Laurent
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supporting information
p. 1396 - 1417
(2022/01/03)
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- Chemical synthesis and biological validation of immobilized protein kinase inhibitory Leucettines
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Leucettines, a family of marine sponge-derived 2-aminoimidazolone alkaloids, are potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). They constitute promising pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome. In order to investigate the scope of potential targets of Leucettine L41, a representative member of the chemical class, we designed an affinity chromatography strategy based on agarose-immobilized leucettines. A synthesis protocol for the attachment of a polyethylene (3 or 4 units) linker to L41 was first established. The linker attachment site on L41 was selected on the basis of the co-crystal structure of L41 with several kinases. L41 was then covalently bound to agarose beads through the primary amine located at the end of the linker. Control, kinase inactive Leucettine was also immobilized, as well as free linker devoid of ligand. Extracts of several mouse tissues revealed a complex pattern of interacting proteins, some of which probably resulting from non-specific, hydrophobic binding, while others representing bona fide Leucettine-interacting proteins. DYRK1A and GSK-3 (glycogen synthase kinase-3) were confirmed as interacting targets by Western blotting in various mouse tissues. The Leucettine affinity chromatography resin constitutes a powerful tool to purify and identify the targets of this new promising therapeutic class of molecules.
- Burgy, Guillaume,Tahtouh, Tania,Durieu, Emilie,Foll-Josselin, Béatrice,Limanton, Emmanuelle,Meijer, Laurent,Carreaux, Fran?ois,Bazureau, Jean-Pierre
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p. 728 - 737
(2013/06/04)
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