Abstract
The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.
MeSH terms
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Binding Sites
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Crystallography, X-Ray
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 1 / chemistry
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 3 / chemistry*
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Models, Molecular
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Molecular Structure
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Protein Binding
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Quantitative Structure-Activity Relationship*
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Stereoisomerism
Substances
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N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(4-(3-chlorophenyl)-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxamide
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Pyrazoles
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Pyrroles
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
Associated data
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PDB/2OJG
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PDB/2OJI
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PDB/2OJJ
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PDB/2OJL
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PDB/ERK2
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PDB/JNK3