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

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.
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https://hal.univ-brest.fr/hal-01517780
Contributor : Olivier Lozach <>
Submitted on : Wednesday, May 3, 2017 - 4:07:14 PM
Last modification on : Friday, October 16, 2020 - 3:41:10 AM

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Christophe Labrière, Olivier Lozach, Mélina Blairvacq, Laurent Meijer, Catherine Guillou. Further investigation of Paprotrain: Towards the conception of selective and multi-targeted CNS kinase inhibitors. European Journal of Medicinal Chemistry, Elsevier, 2016, 124, pp.920 - 934. ⟨10.1016/j.ejmech.2016.08.069⟩. ⟨hal-01517780⟩

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