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P3‐352: Leucettines, a family of pharmacological inhibitors of DYRKs and CLKs derived from the marine sponge: Natural product Leucettamine B
Author(s) -
Tahtouh Tania,
Durieu Emilie,
Carreaux François,
Bazureau JeanPierre,
Meunier Johann,
Maurice Tangui,
Knapp Stefan,
Meijer Laurent
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1577
Subject(s) - dyrk1a , kinase , phosphorylation , natural product , biology , biochemistry , alternative splicing , microbiology and biotechnology , chemistry , gene , gene isoform
We here report on the synthesis, optimization and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on 8 purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative premRNA splicing and Alzheimer’s disease / Down syndrome. Leucettine L41 was co-crystallized with DYRK1A, DYRK2, CLK3 and PIM1. It interacts with key residues located within the ATPbinding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing in a cell based reporting system. The selectivity of Leucettine L41 was extensively studied (kinase activity and interaction assays, affinity chromatography). Leucettine L41 provides protection against glutamate -induced cell death in cultured mouse 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 intracerebroventricular injection of amyloid-# 25-35. Leucettines should be further explored as pharmacological tools to study and modulate preRNA splicing. Leucettines should also be investigated as potential therapeutic drugs in Alzheimer’s disease and in diseases involving abnormal pre-mRNA splicing.