Abstract
The availability of a chemical probe to study the role of a specific domain of a protein in a concentration- and time-dependent manner is of high value. Herein, we report the identification of a highly potent and selective ERK5 inhibitor BAY-885 by high-throughput screening and subsequent structure-based optimization. ERK5 is a key integrator of cellular signal transduction, and it has been shown to play a role in various cellular processes such as proliferation, differentiation, apoptosis, and cell survival. We could demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, which is in contrast to the results obtained by RNAi technology.
MeSH terms
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Apoptosis / drug effects
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Binding Sites
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Cell Differentiation / drug effects
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Cell Line
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Half-Life
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Humans
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Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 7 / metabolism
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Pyridines / chemistry*
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Pyridines / metabolism
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Pyridines / pharmacology
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / pharmacology
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Transcription, Genetic / drug effects
Substances
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Protein Kinase Inhibitors
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Pyridines
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Pyrimidines
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pyrido(3,2-d)pyrimidine
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Mitogen-Activated Protein Kinase 7