Abstract
A new phosphotyrosyl mimetic 4-(alpha-hydroxymalonyl)phenylalanine and its incorporation into a Grb2 SH2 domain-binding tripeptide are presented. In whole-cell studies using malonyl ethyl ester prodrug derivatives, it was observed that the 4-(alpha-hydroxymalonyl)phenylalanyl-containing peptide exhibited greater efficacy than the nonhydroxylated 4-(malonyl)phenylalanyl-containing congener in blocking the association of Grb2 with activated erbB-2 tyrosine kinase. These results are consistent with de-esterification and at least partial intracellular decarboxylation.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / metabolism*
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Cell Line, Tumor
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Drug Design
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Esters / chemical synthesis
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Esters / chemistry
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Esters / pharmacology
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GRB2 Adaptor Protein
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Humans
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Malonates / chemical synthesis*
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Malonates / chemistry
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Malonates / pharmacology
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemical synthesis
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Phenylalanine / chemistry
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Phenylalanine / pharmacology
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Phosphotyrosine / chemistry*
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / pharmacology
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Receptor, ErbB-2 / metabolism
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Structure-Activity Relationship
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Surface Plasmon Resonance
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src Homology Domains*
Substances
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4-(alpha-hydroxymalonyl)phenylalanine
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Adaptor Proteins, Signal Transducing
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Esters
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GRB2 Adaptor Protein
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GRB2 protein, human
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Malonates
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Oligopeptides
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Prodrugs
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Phosphotyrosine
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Phenylalanine
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Receptor, ErbB-2