Planta Med 2012; 78 - PD1
DOI: 10.1055/s-0032-1320359

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

T Tahtouh 1, O Fedorov 2, O Lozach 1, F Carreaux 3, JP Bazureau 3, J Meunier 4, T Maurice 4, S Knapp 2, L Meijer 1, 5
  • 1C.N.R.S., Station Biologique, Roscoff, France
  • 2Structural Genomics Consortium, Oxford, U.K
  • 3Université de Rennes, France
  • 4Université de Montpellier, France
  • 5ManRos Therapeutics, Roscoff, France

We 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.