Design, Synthesis, and Evaluation of Estrogen Sulfotransferase Inhibitors: Potential Enhancers of Tamoxifen-Mediated Apoptosis in ER Negative Breast Cancers

摘要

Small molecule - protein interactions underlie many fundamental processes in biology and provide a basis for pharmacological intervention in human disease. Given that most proteins are only marginally stable, molecular recognition between small molecules and enzyme active sites or protein ligand binding domains (LBDs) often stabilizes protein folding. Ligand-mediated protein stabilization has been recently employed in yeast assays to couple cellular growth to ligand binding of proteins fused to the essential metabolic enzyme dihydrofolate reductase.1 The autocatalytic green fluorescent protein (GFP) from Aequorea victora has also been utilized as a folding reporter that confers a fluorescent signal proportional to the extent of folding of fused proteins. Proteins have also been inserted into loops on the surface of GFP to construct biosensors. Most cellular biosensors of small molecules are based on relatively complex two-hybrid systems, in which ligand binding is used to trigger protein dimerization to activate expression of a reporter gene. However, ideal biosensors would be homogenous (reagentless) and provide a reporter function intrinsic to the sensor molecule without requiring covalent modification or assembly of macromolecular components.