Rational Design of Novel Estrogen Receptor Antagonists

新型雌激素受体拮抗剂的合理设计

基本信息

批准号：
7174671
负责人：
Martin K Safo
金额：
$ 29.16万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174671
关键词：
Address Adverse effects Affinity Agonist Amides Area Binding Biological Assay Breast Cancer Cell Cancer cell line Cell Proliferation Cells Collaborations Competitive Binding Crystallization Development Dimerization Drug Design Drug usage Elements Entropy Enzymes Escherichia coli Estradiol Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Fluorescence Foundations Goals Human Hydroxyl Radical In Vitro Laboratories Lead Length Ligand Binding Ligands MCF7 cell Methods Modification Molecular Molecular Biology Muscle Rigidity NCOA3 gene Numbers Organic Synthesis Protein Overexpression Published Comment Raloxifene Range Reporter Research Research Personnel Resistance development Roentgen Rays Screening procedure Side Solid Source Structure-Activity Relationship System Tamoxifen Testing Tetrahydroisoquinolines Transfection Two-Hybrid System Techniques X-Ray Crystallography Yeasts amino group base carbene computer studies cytotoxicity design fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether hydroxyl group in vitro Assay insight interdisciplinary approach molecular modeling mutant novel programs receptor receptor binding scaffold stem yeast two hybrid system

项目摘要

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.

描述（由申请人提供）：本提案的主要目的是开发和优化新型纯雌激素受体（ER）亚型α拮抗剂。尽管在这一领域做出了巨大努力，但开发选择性 ER 拮抗剂的需求仍未得到满足。我们最初提交的一些研究目标已经完成，为我们修改提案奠定了坚实的基础。我们的建议涉及多学科方法，结合有机合成、分子生物学、X射线晶体学和分子建模方面的专业知识，合理设计和优化作为雌激素受体纯拮抗剂的配体。我们的具体目标包括： (1) 选择性 ER α 拮抗剂的合成：将合成新提出的分子，以优化先导化合物，增强受体水平上结合亲和力的效力和选择性。这样一个全面的合成计划应该会显着增加我们对新型四氢异喹啉支架结构-活性关系的理解； (2) 雌激素拮抗剂的 X 射线晶体学分析：与 F. Rastinejad 博士 (UVA) 合作，对与雌激素受体结合的最有效配体的共晶进行 X 射线分析，将用于探索配体结合并确定纯拮抗剂活性所需的结构特征； (3) 加强和指导先导化合物优化的计算研究：随着结果的展开和定量结构活性关系（SAR），分子建模方法将用于开发新的药物设计策略； (4) 筛选雌激素受体拮抗作用和雌激素受体选择性配体的体外和全细胞测定：将进行各种测定，例如化学发光、基于荧光的竞争性结合、瞬时转染报告基因、酵母二杂交和细胞增殖测定。用于评估所提出化合物的激动剂/拮抗剂活性和细胞毒性。该提案的长期目标是产生和优化作为“纯”α受体拮抗剂的抗雌激素。