Abstract
Grubbs' olefin metathesis reaction was utilized to prepare a macrocyclic variant of a linear Grb2 SH2 domain antagonist in an attempt to induce a beta-bend conformation known to be required for high affinity binding. In extracellular Grb2 SH2 domain binding assays, the macrocyclic analogue exhibited an approximate 100-fold enhancement in binding potency relative to its linear counterpart. The macrocycle was not as effective in whole cell binding assays as would be expected based on its extracellular binding potency.
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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Breast Neoplasms / pathology
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Cell Division / drug effects
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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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Inhibitory Concentration 50
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Models, Molecular
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Molecular Conformation
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Peptides / chemistry*
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Peptides / metabolism
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Protein Binding / physiology
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Proteins / antagonists & inhibitors*
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Proteins / metabolism*
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Receptors, Drug / chemistry*
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Receptors, Drug / metabolism
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Signal Transduction / physiology
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Structure-Activity Relationship
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism*
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Tyrosine / pharmacology*
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src Homology Domains / drug effects*
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src Homology Domains / physiology
Substances
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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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Peptides
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Proteins
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Receptors, Drug
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Tyrosine