Rational Design of Novel Estrogen Receptor Antagonists

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DESCRIPTION (provided by applicant): The main objective of this proposal is to develop and optimize novel and pure estrogen-receptor (ER) subtype alpha antagonists. Despite significant efforts in this area, there is an unmet need for developing selective ER antagonists. Some of our originally submitted research goals have been accomplished and lay a solid foundation for our revised proposal. Our proposal involves a multidisciplinary approach that combines expertise in organic synthesis, molecular biology, X-ray crystallography, and molecular modeling to rationally design and optimize ligands that are pure antagonists of estrogen receptors. Our specific aims include: (1) Synthesis of selective ER alpha antagonists: The new proposed molecules will be synthesized for lead optimization, enhancement of potency and selectivity of binding affinity at the receptor level. Such a comprehensive synthesis program should significantly increase our understanding for structure-activity relationships of the new tetrahydroisoquinoline scaffold; (2) X-ray crystallographic analysis of estrogen antagonists: In collaboration with Dr. F. Rastinejad (UVA), x-ray analyses of co-crystals of most potent ligands bound to the estrogen receptor will be used to explore ligand binding and to identify structural features necessary for pure antagonist activity; (3) Computational studies to enhance and guide lead optimization: Molecular modeling methods will be used to develop new drug design strategies as the results unfold and quantitate structure activity relationships (SAR); (4) In vitro and whole cell assays to screen ligands for estrogen receptor antagonism and estrogen receptor selectivity: Various assays such as a chemiluminescence, fluorescence-based competitive binding, a transient transfection reporter, a yeast two hybrid and a cell proliferation assay will be used to evaluate the agonist/antagonist activity and cytotoxicity of proposed compounds. A long-range goal of this proposal is to generate and optimize antiestrogens that are "pure" alpha-receptor antagonists.