Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2

[Display omitted] The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-06, Vol.24 (12), p.2635-2639
Main Authors: Blake, James F., Gaudino, John J., De Meese, Jason, Mohr, Peter, Chicarelli, Mark, Tian, Hongqi, Garrey, Rustam, Thomas, Allen, Siedem, Christopher S., Welch, Michael B., Kolakowski, Gabrielle, Kaus, Robert, Burkard, Michael, Martinson, Matthew, Chen, Huifen, Dean, Brian, Dudley, Danette A., Gould, Stephen E., Pacheco, Patricia, Shahidi-Latham, Sheerin, Wang, Weiru, West, Kristina, Yin, Jianping, Moffat, John, Schwarz, Jacob B.
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Drug Discovery
Enzyme Activation - drug effects
Erk2 kinase inhibitors
Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors
Hep G2 Cells
Humans
Inhibitory Concentration 50
Mek resistance
Molecular Structure
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Small Molecule Libraries
Structure based drug design
Structure-Activity Relationship
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Summary:[Display omitted] The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.04.068