Abstract
A small peptide mimic of the Grb2-SH2 domain, which was previously prepared through the template-assisted click approach and exhibited selective A431 tumor growth inhibition both in vitro and in vivo, was further elaborated on to enhance the interaction with target phosphorylated proteins. A conformationally fixed analog was efficiently synthesized by solid-supported ring-closing metathesis and Cu(i)/His-mediated self-activating Huisgen [3+2] cycloadditon as the key steps, and exhibited a 10-fold enhanced affinity to a phosphorylated peptide, a truncated peptide analog of the Grb2-SH2-interacting phosphoproteins. A stronger interaction with the target phosphorylated proteins gave this cyclic analog cytotoxic activity in A431 cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding, Competitive
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Cell Line, Tumor
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Cell Survival / drug effects
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Chemistry Techniques, Synthetic
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Cyclization
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Dose-Response Relationship, Drug
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GRB2 Adaptor Protein / chemistry*
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GRB2 Adaptor Protein / metabolism
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Models, Chemical
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Molecular Mimicry
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Molecular Structure
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neoplasms / pathology
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Peptides / chemical synthesis
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Peptides / chemistry*
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Peptides / pharmacology
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / metabolism
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Peptides, Cyclic / pharmacology
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism
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Protein Conformation*
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Xenograft Model Antitumor Assays
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src Homology Domains*
Substances
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GRB2 Adaptor Protein
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Peptides
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Peptides, Cyclic
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Phosphoproteins