Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.

Original publication

DOI

10.1021/jm301034u

Type

Journal article

Journal

J Med Chem

Publication Date

08/11/2012

Volume

55

Pages

9312 - 9330

Keywords

Alkaloids, Amyloid beta-Protein Precursor, Animals, Brain, Cell Death, Cell Line, Chromatography, Affinity, Crystallography, X-Ray, Cyclin-Dependent Kinase 2, Dioxoles, Glutamic Acid, Humans, Imidazoles, In Vitro Techniques, Mice, Models, Molecular, Molecular Structure, Neuroprotective Agents, Porifera, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Stereoisomerism, Structure-Activity Relationship