Abstract
We report a novel series of non-peptide ligands that inhibit the growth factor receptor-bound protein 2 (Grb2)-Src homology 2 (SH2) domain binding, designed using a combined computational and NMR-driven approach. We have identified a new lead compound, 1n (IC(50) = 56 μM), which is cytotoxic in HER2-positive breast cancer cells and disrupts the interaction between HER2 and Grb2. Thus, 1n can be used as a scaffold for the development of efficient Grb2-SH2 domain binding inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Binding, Competitive
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Cell Line, Tumor
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Female
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GRB2 Adaptor Protein / antagonists & inhibitors*
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GRB2 Adaptor Protein / metabolism
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Humans
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Ligands
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / metabolism
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src Homology Domains
Substances
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Antineoplastic Agents
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GRB2 Adaptor Protein
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Ligands
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ERBB2 protein, human
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Receptor, ErbB-2