Novel Ligands and Mechanisms to Achieve Selective Nuclear Receptor Activity

实现选择性核受体活性的新型配体和机制

基本信息

批准号：
9118153
负责人：
JOHN A. KATZENELLENBOGEN
金额：
$ 39.64万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118153
关键词：
3-Dimensional Affinity Alkanesulfonates Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Area Biological Assay Biological Models Blood Vessels Brain Breast Breast Cancer therapy Cardiac Cardiovascular system Cell Nucleus Cell model Cells Clinical Collaborations Conjugated Estrogens Crystallography Dendrimers Development Disease Estradiol Estrogen Receptor beta Estrogen Receptors Estrogen Therapy Estrogens Evaluation Future Goals Health Hormones In Vitro Inflammation Lead Lesion Ligands Mammary Neoplasms Mediating Modeling Molecular Conformation Molecular Models Molecular Probes Multiple Sclerosis Neurons Nuclear Receptors Pathologic Processes Pathology Pathway interactions Pattern Physiological Processes Physiology Process Publishing Receptor Activation Receptor Signaling Regulation Reproductive system Research Research Personnel Resistance Risk Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Steroid Receptors Structure Structure-Activity Relationship Therapeutic Agents Time Tissues Uterine Neoplasms Uterus Work autocrine base bone design endometriosis hormone therapy improved in vivo in vivo Model malignant breast neoplasm member molecular modeling neuroprotection novel novel therapeutics polyglycerol pre-clinical receptor reproductive organ small molecule

项目摘要

DESCRIPTION (provided by applicant): Estrogens, acting through the estrogen receptors, ER� and ER�, control many physiological and pathological processes in numerous target tissues. While progress has been made in developing ER ligands having more desirable patterns of selective activity, such as selective ER modulators (SERMs) and ER-subtype selective ligands, the diversity of modes and pathways through which the ERs act offers intriguing but as yet unexplored mechanisms through which one should be able to obtain new compounds having higher levels of desired selectivity. Our overall goal is to develop potent ER ligands optimized to deliver the full range of desired, long sought-after selectivity in three medically important areas, achieved by three distinct mechanisms: (A) brain neuroprotection mediated through ER� with carefully selected ligands of novel structure; (B) cardiovascular protection afforded by selective activation of extranuclear-initiated ER signaling pathways by estrogen-dendrimer conjugates (EDCs) and small molecules of novel design; and (C) combined anti-proliferative/anti-inflammatory activity as optimized therapy for estrogen-dependent breast cancer and endometriosis, through unique ER conformations induced by structurally novel ligands. Each effort is centered on a distinct mechanistic paradigm and is supported by active, ongoing collaborations with established research groups that should lead to excellent opportunities for further pre-clinical development. Aims: (1) Develop Novel ER� Ligands Having Selective Brain Neuroprotective Activities. A subset of our ER� ligands, acting through an endogenous autocrine anti-inflammatory pathway, is neuroprotective and is active in animal models of multiple sclerosis, reversing established disease. We will develop structure-activity relationships to enhance potency and selectivity of these novel compounds. (2) Develop Novel Pathway-Specific ER Ligands that Afford Selective Vascular, Cardiac, and Bone Protection. Our EDC blocks hormone entry into the nucleus and activates only the extranuclear-initiated ER signaling pathway, yet it provides cardiovascular protection equivalent to that of estradiol without stimulation of uterus or breast tumors. We will develop orally active conjugates with highly stable dendrimers and carefully designed small molecules having pathway selectivity. (3) Develop Novel ER Ligands that Combine Anti- Inflammatory and Anti-Proliferative Activities for Improved Therapy for Endocrine-Resistant Breast Cancers and Endometriosis. Our 3-dimensional ER ligands stabilize a previously unseen ER conformation and inhibit hormone-resistant breast cancer lines and endometriotic lesions. Using structure-guided design, we will develop higher potency and more selective compounds.

描述（由适用提供）：雌激素，通过雌激素受体作用，ER和ER。在许多目标时机中控制许多物理和病理过程。尽管在开发具有更理想的选择活动模式的ER配体方面取得了进展，例如选择性ER调节剂（SERMS）和ER-SUBTYPE选择性配体，但模式和途径的多样性具有吸引人的功能，但随着人们的意想不到的机制，该机制应能够获得更高的选择性选择性的新化合物。我们的总体目标是开发优化的潜在ER配体，以在三个具有医学重要的领域的三个重要领域提供全部所需的，长期的扫描后选择性，这是通过三种不同的机制实现的：（a）通过ER介导的脑神经保护作用，并精心选择了新型结构；（b）通过选择性激活雌激素树状聚合物共轭物（EDCS）和新型设计的小分子来选择性激活外核激发的ER信号通路可提供的心血管保护；（c）通过结构上新型的配体引起的独特ER构象，将抗增殖剂/抗炎活性结合在一起，作为雌激素依赖性乳腺癌和子宫内膜异位症的优化疗法。每项努力都集中在一个独特的机械范式上，并得到与已建立的研究小组的积极，持续的合作的支持，这应该为进一步的临床前开发带来绝佳的机会。目的：（1）开发具有选择性脑神经保护活性的新型ER。通过内源性自分泌抗炎途径起作用的ER-配体的一部分是神经保护性的，并且活跃于多发性硬化症的动物模型中，从而逆转了已建立的疾病。我们将发展结构活性关系，以提高这些新型化合物的效力和选择性。（2）开发出具有选择性血管，心脏和骨骼保护的新型途径特异性ER配体。我们的EDC阻止了同性恋进入核的，并仅激活了核外发起的ER信号通路，但它提供了与雌二醇相当的心血管保护，而不会刺激子宫或乳腺肿瘤。我们将与高度稳定的树枝状聚合物和具有途径选择性的小分子进行口服活跃的偶联物。（3）开发新的ER配体，这些配体结合了抗炎和抗增生剂活性，以改善耐内分泌乳腺癌和子宫内膜异位症的治疗。我们的三维ER配体稳定了先前看不见的ER构象，并抑制了耐骑马的乳腺癌系和子宫内膜损伤。使用结构引导的设计，我们将发展更高的效力和更具选择性的化合物。