Abstract
Synthesis of (2R)-2-carboxymethyl-3-(4-(phosphonomethyl)phenyl) proprionic acid (5) in tert-butyl-protected form (6) and its use for the preparation of a Grb2 SH2 domain-directed tripeptide (8a) is reported. In extracellular ELISA-based assays, 8a exhibits potent Grb2 SH2 domain binding affinity (IC(50)=8 nM). Against cultures of MDA-MB-453 breast cancer cells, which over-express erbB-2 tyrosine kinase, 8a is also antimitogenic at concentrations equivalent to those required to inhibit intracellular association of Grb2 protein with phosphorylated p185(erbB-2) protein (IC(50)=8 microM). Analogue 6 may be useful for the preparation of a variety of phosphatase-stable SH2 domain-directed ligands.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / pathology
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Cell Membrane Permeability / drug effects
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Enzyme-Linked Immunosorbent Assay
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Female
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GRB2 Adaptor Protein
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Humans
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Indicators and Reagents
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Ligands
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Molecular Mimicry
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Phosphoric Monoester Hydrolases / chemistry*
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Phosphotyrosine / chemistry*
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Proteins / drug effects*
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Receptor, ErbB-2 / drug effects
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Receptor, ErbB-2 / metabolism
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Tumor Cells, Cultured
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src Homology Domains / drug effects*
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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GRB2 Adaptor Protein
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GRB2 protein, human
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Indicators and Reagents
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Ligands
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Proteins
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Phosphotyrosine
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Receptor, ErbB-2
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Phosphoric Monoester Hydrolases