Abstract
Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemical synthesis
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Acrylamides / pharmacology*
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Adamantane / chemistry
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Adenine / analogs & derivatives*
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Adenine / chemical synthesis
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Adenine / pharmacology
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Catalytic Domain
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cysteine / chemistry
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Gene Expression Regulation, Neoplastic*
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Humans
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Hydrophobic and Hydrophilic Interactions
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Molecular Docking Simulation
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Molecular Targeted Therapy
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Protein Multimerization
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Proteolysis
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Proto-Oncogene Proteins c-met / chemistry*
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism
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Receptor, ErbB-2 / chemistry*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-3 / antagonists & inhibitors*
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Receptor, ErbB-3 / chemistry
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Receptor, ErbB-3 / genetics
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Signal Transduction
Substances
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Acrylamides
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Antineoplastic Agents
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Protein Kinase Inhibitors
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TX1-85-1
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Adenosine Triphosphate
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ERBB2 protein, human
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ERBB3 protein, human
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Proto-Oncogene Proteins c-met
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Receptor, ErbB-2
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Receptor, ErbB-3
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Adenine
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Cysteine
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Adamantane