Leucettines, a family of pharmacological inhibitors of DYRKs and CLKs kinases derived from the marine sponge Leucettamine B

International audienceWe here report on leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues, followed by activity testing on 8 purified kinases led to highly potent inhibitors of CLKs & DYRKs, two families of kinases involved in pre-mRNA splicing and Alzheimer's disease. Leucettine L41 was co-crystallized with DYRK1A, -2, CLK3 and PIM1. Leucettine L41 inhibits phosphorylation of pre-RNA splicing regulating Ser/Arg-rich proteins. Leucettine L41 modulates alternative pre-mRNA splicing in a cellular systems. The selectivity of Leucettine L41 was extensively characterized. Leucettine L41 provides protection against glutamate-induced cell death in cultured HT22 hippocampal cells. It also provides neuroprotection against APP-induced cell death in mouse brain slices. Finally it prevents in vivo cognitive impairments due to icv injection of amyloid-β 25-35. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines should also be investigated as potential therapeutic drugs in Alzheimer's disease and in diseases involving abnormal pre-mRNA splicing

Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B.

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