Leucettines, a family of pharmacological inhibitors of DYRKs & CLKs kinases derived from the marine sponge Leucettamine B - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Planta Medica Année : 2012

Leucettines, a family of pharmacological inhibitors of DYRKs & CLKs kinases derived from the marine sponge Leucettamine B

T. Tahtouh
  • Fonction : Auteur
O. Fedorov
  • Fonction : Auteur
O. Lozach
  • Fonction : Auteur
J. Meunier
  • Fonction : Auteur
T. Maurice
  • Fonction : Auteur
S. Knapp
  • Fonction : Auteur
L. Meijer
  • Fonction : Auteur

Résumé

We here report on leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues, followed by activity testing on 8 purified kinases led to highly potent inhibitors of CLKs & DYRKs, two families of kinases involved in pre-mRNA splicing and Alzheimer's disease. Leucettine L41 was co-crystallized with DYRK1A, -2, CLK3 and PIM1. Leucettine L41 inhibits phosphorylation of pre-RNA splicing regulating Ser/Arg-rich proteins. Leucettine L41 modulates alternative pre-mRNA splicing in a cellular systems. The selectivity of Leucettine L41 was extensively characterized. Leucettine L41 provides protection against glutamate-induced cell death in cultured HT22 hippocampal cells. It also provides neuroprotection against APP-induced cell death in mouse brain slices. Finally it prevents in vivo cognitive impairments due to icv injection of amyloid-β 25-35. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines should also be investigated as potential therapeutic drugs in Alzheimer's disease and in diseases involving abnormal pre-mRNA splicing.

Domaines

Chimie organique
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Dates et versions

hal-00870776 , version 1 (08-10-2013)

Identifiants

Citer

T. Tahtouh, O. Fedorov, O. Lozach, François Carreaux, Jean-Pierre Bazureau, et al.. Leucettines, a family of pharmacological inhibitors of DYRKs & CLKs kinases derived from the marine sponge Leucettamine B. Planta Medica, 2012, 78, pp.PD1. ⟨10.1055/s-0032-1320359⟩. ⟨hal-00870776⟩
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