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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.

Original publication

DOI

10.1021/jm200274d

Type

Journal article

Journal

J Med Chem

Publication Date

23/06/2011

Volume

54

Pages

4172 - 4186

Keywords

Alternative Splicing, Animals, Aquatic Organisms, Benzodioxoles, Crystallography, X-Ray, Cyclin-Dependent Kinases, Endothelial Cells, Humans, Imidazolines, Microvessels, Models, Molecular, Nuclear Proteins, Phosphorylation, Porifera, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Quantitative Structure-Activity Relationship, RNA Precursors, RNA-Binding Proteins, Serine-Arginine Splicing Factors, Stereoisomerism