EXPLORE SUBTYPE SELECTIVE ESTROGEN RECEPTOR RESPONSES: BREAST CA, OSTEOPOROSIS

探索亚型选择性雌激素受体反应：乳腺癌、骨质疏松症

• 批准号: 6347944
• 负责人: ROSS V WEATHERMAN
• 金额: $ 0.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347944
• 关键词: biological products; biomedical resource; enzymes; proteins

One of the signature characteristics of drugs targeting the estrogen receptor is a marked difference in the effect of the drug in different tissues. A good example is the breast cancer drug tamoxifen which shows antagonist effects in breast tissue but agonist effects in uterine, bone and cardiovascular tissue. Other drugs have different tissue profiles. Our lab has identified one possible molecular mechanism behind these differences. The two subtypes of the estrogen receptor (ER-alpha and ER-beta) have different responses to estradiol, tamoxifen and raloxifene at an AP-1 response element. My project is to determine the key structural features on the ligands and receptors responsible for these differences using hybrids of the receptor as well as hybrid molecules. Crystal structures have been reported for ER-alpha bound to estradiol, raloxifene and tamoxifen. The Computer Graphics Laboratory facilities allows me to use these structures to assist in my ligand design as well as to assess possible interactions with new compounds that I have made.

靶向药物的特征之一是 雌激素受体是一个显着的差异，在药物的作用， 不同的组织 一个很好的例子是乳腺癌药物他莫昔芬 其在乳腺组织中显示拮抗剂作用，但在 子宫、骨骼和心血管组织。 其他药物有不同的 组织轮廓 我们的实验室发现了一种可能的分子 这些差异背后的机制。 雌激素的两种亚型 受体（ER-α和ER-β）对雌二醇具有不同的反应， 他莫昔芬和雷洛昔芬。 我的项目是 来确定配体和受体的关键结构特征 负责这些差异使用杂交的受体， 以及混合分子。 晶体结构已经报道用于 ER-α与雌二醇、雷洛昔芬和他莫昔芬结合。 计算机 图形实验室设施允许我使用这些结构来 帮助我设计配体，并评估可能的相互作用， 用我做的新化合物。