Abstract B197: Understanding the mechanism of action of small molecules that restore E-cadherin expression.

摘要: E-cadherin is a transmembrane protein that maintains intercellular contacts and cellular polarity in epithelial tissues. The down-regulation of thought to aid the induction an epithelial-to-mesenchymal transition (EMT) resulting increased potential for invasion into surrounding tissues entry bloodstream. Loss has been observed variety human tumors from somatic mutations, chromosomal deletions, proteolytic cleavage E-cadherin, most commonly silencing CDH1 gene promoter. A novel High Throughput Screen was developed identify small molecules restored expression SW620 cell line followed by medicinal chemistry employing iterative analog library synthesis better structure-activity relationship (SAR). Preliminary optimization screening hit shown it possible synthesize have improved ability restore compared initial hits. This restoration confirmed visualization at membrane via immunofluorescent microscopy. Further biological analysis profiled analogs minimal effect on proliferation, but decrease invasion. Recent endeavors taken elucidate mechanism action these expression. Quantitative PCR treatment with selected increases mRNA ∼50 fold after 16 hours suggesting are altering transcription gene. supported experiments conducted using plasmid construct containing 1400bp fragment promoter luciferase reporter. After transfection, cells were treated compounds, lysed, activity measured. It active had significant increase as DMSO or dead molecule, which used controls. More specifically, this suggests specifically effecting within region Future work will include truncating narrow down portion targeted molecules, hopes specific binding sites be present region. Elucidation identifying molecular target. Such information would allow further development more efficacious potent well research understand importance interaction role EMT therapeutic In addition, combinatorial treatments sub-therapeutic doses standard care chemotherapeutics clinic our screened synergistic effects proliferation apoptosis assays. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings AACR-NCI-EORTC International Conference: Molecular Targets Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Ther 2011;10(11 Suppl):Abstract nr B197.