Novel Ligands and Mechanisms to Achieve Selective Nuclear Receptor Activity

描述（由申请人提供）：雌激素，通过雌激素受体ER和ER，控制许多靶组织的许多生理和病理过程。虽然在开发具有更理想的选择性活性模式的内质网配体方面取得了进展，例如选择性内质网调节剂（SERMs）和内质网亚型选择性配体，但内质网作用的模式和途径的多样性提供了有趣但尚未探索的机制，通过这些机制，人们应该能够获得具有更高期望选择性水平的新化合物。我们的总体目标是开发有效的内质网配体，通过三种不同的机制，在三个重要的医学领域优化提供全方位的期望，长期追求的选择性：(A)通过内质网介导的脑神经保护-精心挑选的新型结构配体；(B)通过雌激素-树突状聚合物偶联物（EDCs）和新设计的小分子选择性激活核外启动的内质网信号通路提供心血管保护；(C)结合抗增殖/抗炎活性，通过结构新颖的配体诱导独特的ER构象，作为雌激素依赖性乳腺癌和子宫内膜异位症的优化治疗方法。每一项努力都集中在一个独特的机制范式上，并得到与已建立的研究小组积极、持续的合作的支持，这将为进一步的临床前开发带来极好的机会。目的：(1)开发具有选择性脑神经保护活性的新型ER配体。我们的ER配体的一个子集，通过内源性自分泌抗炎途径起作用，具有神经保护作用，并在多发性硬化症动物模型中活跃，逆转既定疾病。我们将发展结构-活性关系，以提高这些新化合物的效力和选择性。(2)开发新的通路特异性内质网配体，提供选择性血管、心脏和骨骼保护。我们的EDC阻断激素进入细胞核，仅激活核外启动的内质网信号通路，但它提供了相当于雌二醇的心血管保护，而不会刺激子宫或乳房肿瘤。我们将开发具有高度稳定的树状大分子和精心设计的具有途径选择性的小分子的口服活性偶联物。(3)开发新型ER配体，结合抗炎和抗增殖活性，改善内分泌抵抗性乳腺癌和子宫内膜异位症的治疗。我们的三维内质网配体稳定了以前未见过的内质网构象，并抑制激素抗性乳腺癌细胞系和子宫内膜异位症病变。利用结构导向设计，我们将开发出更高效力和更具选择性的化合物。

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.