Further investigation of Paprotrain: Towards the conception of selective and multi-targeted CNS kinase inhibitors
| Autor: | Mélina Blairvacq, Olivier Lozach, Christophe Labrière, Laurent Meijer, Catherine Guillou |
|---|---|
| Přispěvatelé: | Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ManRos Therapeutics, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DYRK1B Subfamily DYRK1A Photochemistry Drug Evaluation Preclinical [CHIM.THER]Chemical Sciences/Medicinal Chemistry 01 natural sciences KB Cells CLK1 03 medical and health sciences Alzheimer Disease Drug Discovery Humans Phosphorylation Protein Kinase Inhibitors Dual & selective inhibitors Pharmacology Paprotrain 010405 organic chemistry Kinase Chemistry Cyclin-dependent kinase 5 Organic Chemistry Multi-targeted General Medicine DYRKs 11H-pyridocarbazole Alzheimer's disease 3. Good health 0104 chemical sciences 030104 developmental biology Biochemistry Cdc2-like kinases Kinesin Protein Kinases |
| Zdroj: | European Journal of Medicinal Chemistry European Journal of Medicinal Chemistry, Elsevier, 2016, 124, pp.920-934. ⟨10.1016/j.ejmech.2016.08.069⟩ European Journal of Medicinal Chemistry, 2016, 124, pp.920-934. ⟨10.1016/j.ejmech.2016.08.069⟩ |
| ISSN: | 0223-5234 1768-3254 |
| DOI: | 10.1016/j.ejmech.2016.08.069⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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