Abstract
The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.
MeSH terms
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Drug Design*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
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Extracellular Signal-Regulated MAP Kinases / chemistry
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Models, Molecular
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Molecular Conformation*
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Pyrroles / chemistry*
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Pyrroles / pharmacology*
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Substrate Specificity
Substances
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Protein Kinase Inhibitors
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Pyrroles
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Extracellular Signal-Regulated MAP Kinases
Associated data
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PDB/3I4B
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PDB/3I5Z
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PDB/3I60