Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach.
So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3β, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
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Tell
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Hilbrich
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Holzer
Frank
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Totzke
Christoph
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Schachtele
Inna
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Slynko
Wolfgang
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Sippl
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. hilgeroth@pharmazie.uni-halle.de.
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Hilgeroth
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014162:Transfection; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D048053:Mitogen-Activated Protein Kinase 6