Further investigation of Paprotrain: Towards the conception of selective and multi-targeted CNS kinase inhibitors.
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.
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.
Christophe
C
Labrière
'Protein Phosphorylation & Human Disease' Group, Station Biologique, B. P. 74, 29682, Roscoff Cedex, Bretagne, France.
Olivier
O
Lozach
'Protein Phosphorylation & Human Disease' Group, Station Biologique, B. P. 74, 29682, Roscoff Cedex, Bretagne, France.
Mélina
M
Blairvacq
Manros Therapeutics, Centre de Perharidy, 29680, Roscoff, France.
Laurent
L
Meijer
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.
Catherine
C
Guillou
D000544:Alzheimer Disease / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007624:KB Cells; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases
11H-pyridocarbazole; Alzheimer's disease; Cdc2-like kinases; DYRKs; Dual & selective inhibitors; Multi-targeted; Paprotrain; Photochemistry