Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 21, Pages 9312-9330Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301034u
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Funding
- Fonds Unique Interministeriel (FUI) PHARMASEA project
- Association France-Alzheimer (Finistere)
- CRITT-Sante Bretagne
- Fondation Jerome Lejeune
- Anna's Angels Down Syndrome Research Foundation
- Caroline Ball Family Fund
- Canadian Institutes for Health Research [1097737]
- Canada Foundation for Innovation, Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust
- Takeda
- Cancer Research UK [14532] Funding Source: researchfish
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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 leucetttamine 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-3 beta. 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.
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