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Molecules. 2018 Sep 12;23(9). pii: E2335. doi: 10.3390/molecules23092335.

Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay.

Author information

1
Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany. max.holzer@medizin.uni-leipzig.de.
2
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. nico.schade@pharmazie.uni-halle.de.
3
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. ansgar.opitz@pharmazie.uni-halle.de.
4
Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany. isabel.hilbrich@medizin.uni-leipzig.de.
5
Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany. jens.stieler@medizin.uni-leipzig.de.
6
Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany. tim.vogel.le@gmail.com.
7
Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany. valentina.neukel@hs-furtwangen.de.
8
Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany. moritz.oberstadt@medizin.uni-leipzig.de.
9
ProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, Germany. f.totzke@proqinase.com.
10
ProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, Germany. c.schaechtele@proqinase.com.
11
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. wolfgang.sippl@pharmazie.uni-halle.de.
12
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. andreas.hilgeroth@pharmazie.uni-halle.de.

Abstract

The current number of drugs available for the treatment of Alzheimer's disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau⁻tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges.

KEYWORDS:

AD drug discovery; derivatives; lead structure; structure-activity; synthesis

PMID:
30213139
DOI:
10.3390/molecules23092335
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