Abstract
Although considerable effort has been devoted to developing Grb2 SH2 domain-binding antagonists, important questions related to ligand specificity, and identification of intracellular targets remain unanswered. In order to begin addressing these issues, the design, synthesis, and evaluation of a novel biotinylated macrocycle are reported that bears biotin functionality at a C-terminal rather than the traditional N-terminal position. With a Grb2 SH2 domain-binding K(eq) value of 3.4 nM, the title macrocycle (5) is among the most potent biotinylated SH2 domain-binding ligands yet disclosed. This should be a useful tool for elucidating physiological targets of certain Grb2 SH2 domain-binding antagonists.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Biotinylation
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Breast Neoplasms / metabolism
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Cyclization
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Female
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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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Peptide Fragments / chemical synthesis*
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism*
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Phosphotyrosine / chemistry*
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Protein Binding
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Receptor, ErbB-2 / metabolism*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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src Homology Domains*
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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Ligands
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Peptide Fragments
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Phosphotyrosine
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Receptor, ErbB-2