Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. - Université Pierre et Marie Curie Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2011

Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing.

Meera Soundararajan
  • Fonction : Auteur
Oleg Fedorov
  • Fonction : Auteur
Panagis Filippakopoulos
  • Fonction : Auteur
Olivier Lozach
Lucie Babault
  • Fonction : Auteur
Blandine Baratte
Yasushi Ogawa
  • Fonction : Auteur
Masatoshi Hagiwara
  • Fonction : Auteur
Andreas Eisenreich
  • Fonction : Auteur
Ursula Rauch
  • Fonction : Auteur

Résumé

We here report on the synthesis, optimization, and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on eight purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative pre-mRNA splicing and Alzheimer's disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts with key residues located within the ATP-binding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing, in a cell-based reporting system. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines may also be investigated as potential therapeutic drugs in Alzheimer's disease (AD) and in diseases involving abnormal pre-mRNA splicing.

Domaines

Chimie organique
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Dates et versions

hal-00870007 , version 1 (04-10-2013)

Identifiants

Citer

Mansour Debdab, François Carreaux, Steven Renault, Meera Soundararajan, Oleg Fedorov, et al.. Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing.. Journal of Medicinal Chemistry, 2011, 54 (12), pp.4172-86. ⟨10.1021/jm200274d⟩. ⟨hal-00870007⟩
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