The broad, long-term objective of this proposal is the development of new and more effective therapeutic agents for the treatment of breast cancer by enhancing the understanding of one of the key interactions between 17alpha-substituted estrogens and the ER-Hormone Binding Domain.
The specific aims for this project are: 1). the synthesis of four selected series of high affinity estradiols, 2). the determination of their molecular conformation, 3). the determination of receptor affinity and activity, 4). correlation of observed biological responses with the calculated ligand-receptor structure, especially the AF-2 (helix 12) region, 5). iterative ligand design and refinement of the hypothesis. The health relatedness of this project is that it will contribute to the development of better therapeutic agents for breast cancer in women and expand the understanding of the steps in the estrogenic response. The research design begins with the underlying hypothesis which proposes that appropriately 17alpha-substituted estrogens interact with the critical helix 12 of the receptor. The synthetic chemistry yields new compounds (probes) which undergo both conformational analyses and biological assays. These results are evaluated, leading to improved ligands and/or a refined hypothesis. These steps will utilize: 1). stereochemically controlled and versatile synthetic methods, 2). determination of ligand conformations by using high field NMR correlations and molecular modeling, 3). competitive receptor binding and functional assays to determine biological properties, and 4). quantitative-structure activity relationships and molecular docking to correlate the observed and predicted results. The conclusions will aid in the design of better second generation ligands and the development of a better hypothesis for the interactions of the hormone-receptor-effector complex.
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