Estrogen Receptor Coligand Reprogramming of Menopausal Hormone Therapy

 描述(由申请人提供)：我们的目标是发现药物，将使更年期激素治疗(MHT)安全的长期治疗与更年期相关的慢性疾病。由于女性的寿命越来越长，更年期已成为女性健康的一个关键问题。女性的预期寿命现在是81.2岁。与仅仅一个世纪前不同的是，大多数女性将进入更年期，并在绝经后生活大约三分之一的时间。目前，美国有3600万更年期女性，预计这一数字将在25年内飙升至约5000万。不幸的是，更年期与骨质疏松症、肥胖症、糖尿病和代谢综合征的发病率增加有关。长期暴露于MHT可降低这些情况的风险。MHT被批准用于短期治疗潮热和阴道/外阴症状，因为长期使用MHT与乳腺癌、心血管疾病和阿尔茨海默病的风险增加有关。如果能够为长期治疗开发更安全的MHT方案，将在妇女健康初级预防方面取得重大突破。我们发现了一种名为ERαColigand的化合物，它重新编程了雌二醇对基因表达和细胞增殖的影响。我们的数据表明，ERαColigand以a的速度与ERα表面结合 与雌激素分离结合部位，导致E2与其结合部位的结合增加。这两种配体同时与ERα结合会引起构象的变化，这从ERα的熔融温度的变化中可见一斑。这些研究表明，E2-ERα-ER配体复合体的构象不同于E2-ERα复合体，导致E2转录和细胞效应的重新编程。事实上，我们发现 E2/ERαColigand组合对E2进行重新编程，以调节U2OS细胞中800多个独特的基因。这些基因不受E2或ERα结合的单独调控。众所周知，雌激素通过与ERα结合，激活c-myc等癌基因，从而刺激乳腺癌细胞的增殖。我们发现ERαColigand对ERα进行了重新编程，因此E2不再导致细胞增殖，也不刺激c-myc的产生。ERαColigand还阻断了E2对小鼠子宫生长的刺激作用。基于这些发现，我们假设ERαColigand可以与用于甲亢的现有雌激素联合使用，以阻断E2的不利增殖作用，从而允许ERαColigand/雌激素组合安全地用于MHT的长期治疗。这一第一阶段提案的目的是选择一种在培养细胞和动物中具有最佳安全性的领先ERαColigand/雌激素组合，然后在第二阶段提案中将其推进到药代动力学/药效学和其他临床前测试。这些研究有可能促进一种新型MHT的早期开发，这种药物可用于长期服用，以预防与更年期相关的慢性疾病，如骨质疏松症、肥胖、糖尿病和代谢综合征。

 DESCRIPTION (provided by applicant): Our goal is to discover drugs that will make menopausal hormone therapy (MHT) safe for long-term treatment of chronic conditions associated with menopause. Due to the increasing longevity of women, menopause has become a critical issue in Women's Health. Life expectancy for women is now 81.2 years. Unlike just a century ago, most women will reach menopause and live approximately one-third of their life after menopause. There are currently 36 million menopausal women in the U.S. and the number is projected to soar to about 50 million in 25 years. Unfortunately, menopause is associated with an increase in the incidence of osteoporosis, obesity, diabetes and metabolic syndrome. Long term exposure to MHT decreases the risk of these conditions. MHT is approved for short-term treatment of hot flashes and vaginal/vulvar symptoms, since long-term treatment with MHT is associated with an increased risk of breast cancer, cardiovascular risks and Alzheimer's disease. A major breakthrough in primary prevention for Women's Health would occur if safer MHT regimens could be developed for long-term treatment. We discovered compounds termed ERα coligands that reprogram the effects of estradiol on gene expression and cell proliferation. Our data indicate that the ERα coligand binds to the surface of ERα, at a separate binding site than estrogens, leading to an increase in binding of E2 to its binding site. The binding of both ligands simultaneously to ERα produces a change in conformation as demonstrated by an alteration in the melting temperature of ERα. These studies indicate that the conformation of the E2-ERα-ER coligand complex is distinct from the E2-ERα complex leading to the reprogramming of the E2 transcriptional and cellular effects. In fact, we found that the E2/ERα coligand combination reprograms E2 to regulate over 800 unique genes in U2OS cells. These genes are not regulated by E2 or the ERα coligand alone. It is well established that E2 stimulates the proliferation of MCF-7 breast cancer cells by binding to ERα resulting in the activation of oncogenes, such as c-MYC. We found that the ERα coligand reprograms ERα so E2 no longer causes cell proliferation, nor does it stimulate c-MYC production. The ERα coligand also blocked E2 stimulation of uterine growth in mice. Based on these findings, we hypothesize that ERα coligands can be combined with existing estrogens, used in MHT, to block the adverse proliferative action of E2 to allow the ERα coligand/estrogen combination to be used safely for long-term MHT treatment. The aim of this phase I proposal is to select a lead ERα coligand/estrogen combination that has the best safety profile in cultured cells and animals prior to advancing it to Pharmacokinetic/Pharmacodynamic and other pre-clinical testing in a phase II proposal. These studies have the potential to facilitate the early development of a new type of MHT, that can be used for long-term administration, to prevent chronic diseases associated with menopause, such as osteoporosis, obesity, diabetes and metabolic syndrome.