Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues.
Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues.
复制标题
DOI：
10.1126/scisignal.aad8170
复制
发表时间：
2016-05-24
影响因子：
7.3
通讯作者：
Katzenellenbogen BS
中科院分区：
文献类型：
--
作者：
Madak-Erdogan Z;Kim SH;Gong P;Zhao YC;Zhang H;Chambliss KL;Carlson KE;Mayne CG;Shaul PW;Korach KS;Katzenellenbogen JA;Katzenellenbogen BS
具有良好药理学特征的雌激素在医学上有很大的需求，其支持绝经期妇女所需的活性，如代谢和血管保护，但缺乏对乳房和子宫的刺激活性。在这里，我们报告的发展结构新颖的雌激素，优先激活雌激素受体（ER）信号通路的一个子集，并导致有利的靶组织选择性活性。通过改变雌激素配体的结构，保留其基本的化学和物理特性，但大大降低了它们与ER的结合亲和力，我们获得了“途径优先雌激素”（PaPEs），其与ER相互作用，优先激活细胞核启动的信号通路。PaPE引发了一种基因调控模式以及细胞和生物学过程，不会刺激生殖和乳腺组织或乳腺癌细胞。然而，在卵巢切除小鼠中，PaPE在代谢组织（脂肪组织和肝脏）中引发了有益的反应，减少了体重增加和脂肪积累，并在血管系统中加速了内皮损伤的修复。这种设计配体结构改变的过程代表了一种新的方法来开发配体，该配体改变ER介导的胞核和核途径的平衡，以获得组织选择性的、非核途径优先的雌激素，这可能有利于绝经后激素替代。该方法也可能对核激素受体超家族的其他成员具有广泛的适用性。
There is great medical need for estrogens with favorable pharmacological profiles, that support desirable activities for menopausal women such as metabolic and vascular protection but that lack stimulatory activities on the breast and uterus. Here, we report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained “Pathway Preferential Estrogens” (PaPEs) which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear pathway-preferential estrogens, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily.