2. Academic Validation
  3. 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

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

  • J Med Chem. 2011 Jun 23;54(12):4172-86. doi: 10.1021/jm200274d.
Mansour Debdab 1,  François Carreaux,  Steven Renault,  Meera Soundararajan,  Oleg Fedorov,  Panagis Filippakopoulos,  Olivier Lozach,  Lucie Babault,  Tania Tahtouh,  Blandine Baratte,  Yasushi Ogawa,  Masatoshi Hagiwara,  Andreas Eisenreich,  Ursula Rauch,  Stefan Knapp,  Laurent Meijer,  Jean-Pierre Bazureau
Affiliations

Affiliation

  • 1 Université de Rennes 1, Sciences Chimiques de Rennes, UMR CNRS 6226, Groupe Ingénierie Chimique & Molécules pour le Vivant (ICMV), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes cedex, France.
PMID: 21615147 DOI: 10.1021/jm200274d
Abstract

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.

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