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 β和ER β起作用，控制许多靶组织中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ER配体（例如选择性ER调节剂（SERM）和ER亚型选择性配体）方面已经取得了进展，但ER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，通过该机制人们应该能够获得具有更高水平的所需选择性的新化合物。我们的总体目标是开发有效的ER配体，优化以在三个医学重要领域提供全方位的所需的，长期追求的选择性，通过三种不同的机制实现：（A）通过ER介导的脑神经保护与精心选择的新结构配体;（B）通过雌激素-树枝状聚合物缀合物（EDCs）选择性激活雌激素核起始的ER信号传导途径提供的心血管保护和新设计的小分子;和（C）通过由结构新颖的配体诱导的独特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疗法的组合抗增殖/抗炎活性。每一项工作都以独特的机制范式为中心，并得到与已建立的研究小组积极、持续合作的支持，这将为进一步的临床前开发带来绝佳的机会。目的：（1）开发具有选择性脑保护活性的新型ER β配体。我们的ER β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，在多发性硬化症的动物模型中具有活性，可逆转已建立的疾病。我们将开发结构-活性关系，以提高这些新型化合物的效力和选择性。(2)开发新型通路特异性ER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，仅激活细胞核启动的ER信号通路，但它提供的心血管保护相当于雌二醇，而不会刺激子宫或乳腺肿瘤。我们将开发具有高度稳定的树枝状聚合物和精心设计的具有通路选择性的小分子的口服活性缀合物。(3)开发新型ER配体，结合联合收割机抗炎和抗肿瘤活性，用于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ER配体稳定了以前看不见的ER构象，并抑制了乳腺癌耐药株和乳腺癌病变。使用结构导向设计，我们将开发更高效能和更有选择性的化合物。

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.