Abstract
Macrocyclization from the phosphotyrosyl (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Binding Sites
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Cell Line, Tumor
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Cyclization
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Drug Design
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Enzyme-Linked Immunosorbent Assay
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GRB2 Adaptor Protein
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Humans
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Ligands
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Models, Molecular
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Molecular Mimicry
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Oligopeptides / chemistry*
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Peptides, Cyclic / chemical synthesis*
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology
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Proteins / metabolism*
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Receptor, ErbB-2 / metabolism
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src Homology Domains*
Substances
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3-(2-amino-2-oxoethyl)-1,4,7-triaza-10-(4-(dicarboxymethyl)phenyl)-14-(1-naphthyl)-2,5,8-trioxo-6-pentamethylenecyclopentadecane-9-acetic acid
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Adaptor Proteins, Signal Transducing
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GRB2 Adaptor Protein
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GRB2 protein, human
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Ligands
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Oligopeptides
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Peptides, Cyclic
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Proteins
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Receptor, ErbB-2