Abstract
Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of beta-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a beta-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates beta-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.
MeSH terms
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Adenomatous Polyposis Coli / genetics
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Adenomatous Polyposis Coli / metabolism
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism*
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Antineoplastic Agents / therapeutic use
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Apoptosis / physiology
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / metabolism*
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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Cell Line
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Colon / anatomy & histology
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Gene Expression Regulation*
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Inhibitor of Apoptosis Proteins
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Lymphoid Enhancer-Binding Factor 1
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Male
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Mice
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Mice, Inbred C57BL
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Molecular Structure
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Neoplasm Proteins
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Pyrimidinones / chemistry
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Pyrimidinones / metabolism*
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Pyrimidinones / therapeutic use
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Signal Transduction / physiology
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Survivin
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic*
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beta Catenin
Substances
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Antineoplastic Agents
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BIRC5 protein, human
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Bridged Bicyclo Compounds, Heterocyclic
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CTNNB1 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Cytoskeletal Proteins
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DNA-Binding Proteins
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ICG 001
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Inhibitor of Apoptosis Proteins
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Lymphoid Enhancer-Binding Factor 1
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Pyrimidinones
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Survivin
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Trans-Activators
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Transcription Factors
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beta Catenin
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Cyclin D1