Leucettine L41

Description

Leucettine L₄₁ is an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), DYRK2, CDC-like kinase 1 (CLK1), and CLK3 (IC₅₀s = 0.04, 0.035, 0.015, and 4.5 μM, respectively).¹ It also inhibits GSK3α/β and Pim1 with IC₅₀ values of 0.41 and 4.1 μM, respectively. It inhibits phosphorylation of the serine/arginine (SR) protein 9G8 by DYRK2, DYRK3, CLK1, CLK2, and CLK4 and inhibits TNF-α-induced SRp75 and SRp55 phosphorylation in human microvascular endothelial cells when used at concentrations ranging from 0.1 to 10 μM. Leucettine L₄₁ modulates alternative pre-RNA splicing of a synthetic CLK1 minigene in a reporter model. It prevents lipid peroxidation and the accumulation of reactive oxygen species (ROS) induced by amyloid-β 25-35 in the hippocampus in a mouse model of Alzheimer’s disease-like toxicity.² Leucettine L₄₁ (0.4, 1.2, and 4 μg, i.c.v.) also prevents memory deficits induced by amyloid-β 25-35 in the same model.

References

1. Debdab, M., Carreaux, F., Renault, S., et al. 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. 54(12),4172-4186(2011).
2. Naert, G., Ferré, V., Meunier, J., et al. Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ₂5-35 peptide administration in mice Eur. Neuropsychopharmacol. 25(11),2170-2182(2015).