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Eur J Med Chem. 2016 Nov 29;124:920-934. doi: 10.1016/j.ejmech.2016.08.069. Epub 2016 Aug 31.

Further investigation of Paprotrain: Towards the conception of selective and multi-targeted CNS kinase inhibitors.

Author information

1
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France. Electronic address: christophe.labriere@gmail.com.
2
'Protein Phosphorylation & Human Disease' Group, Station Biologique, B. P. 74, 29682, Roscoff Cedex, Bretagne, France.
3
Manros Therapeutics, Centre de Perharidy, 29680, Roscoff, France.
4
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France. Electronic address: catherine.guillou@cnrs.fr.

Abstract

Starting from a known compound, identified as the first inhibitor of the kinesin MKLP-2 and named Paprotrain, we have investigated its reactivity to produce through photochemistry a potent nanomolar inhibitor of the kinase DYRK1A. Using similar and different chemical pathways, we have designed several families of compounds that have been screened on a panel of five protein kinases: CK1δ/ε, CDK5/p25, GSK3α/β, DYRK1A and CLK1, all involved in neurodegenerative disorders such as Alzheimer's disease. We have identified a first group of multi-targeted compounds, a second group of dual inhibitors of DYRK1A & CLK1 and a last group of selective inhibitors of CLK1. Then, our best submicromolar to nanomolar inhibitors were evaluated towards the closest members of the aforementioned kinases: DYRK1B and CLK4, as well as the subfamily CLK2-3. Several compounds appear to be particularly promising for the development of tools in the battle against Alzheimer's disease.

KEYWORDS:

11H-pyridocarbazole; Alzheimer's disease; Cdc2-like kinases; DYRKs; Dual & selective inhibitors; Multi-targeted; Paprotrain; Photochemistry

PMID:
27676471
DOI:
10.1016/j.ejmech.2016.08.069
[Indexed for MEDLINE]

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