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）安全的长期治疗慢性疾病与更年期。由于女性寿命的增加，更年期已成为女性健康的一个关键问题。妇女的预期寿命现在是81.2岁。与仅仅一个世纪前不同，大多数女性将进入更年期，更年期后的寿命约为她们生命的三分之一。美国目前有3600万更年期妇女，预计25年内这一数字将飙升至约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可降低这些疾病的风险。MHT被批准用于潮热和阴道/外阴症状的短期治疗，因为长期使用MHT治疗与乳腺癌，心血管风险和阿尔茨海默病的风险增加有关。如果能够开发出更安全的MHT方案用于长期治疗，那么妇女健康初级预防方面将出现重大突破。我们发现了称为ERα共配体的化合物，其重新编程雌二醇对基因表达和细胞增殖的影响。我们的数据表明，ERα共配体结合到ERα的表面，在一个 单独的结合位点，导致E2与其结合位点的结合增加。两种配体同时与ERα结合会引起构象变化，如ERα解链温度的改变所示。这些研究表明，E2-ERα-ER共配体复合物的构象与E2-ERα复合物不同，导致E2转录和细胞效应的重编程。事实上，我们发现 E2/ERα共配体组合重新编程E2以调节U2 OS细胞中超过800个独特基因。这些基因不受E2或ERα共配体单独调控。已经确定，E2通过与ERα结合刺激MCF-7乳腺癌细胞增殖，导致癌基因（如c-MYC）活化。我们发现ERα共配体重新编程ERα，因此E2不再引起细胞增殖，也不刺激c-MYC的产生。ERα配体还阻断E2对小鼠子宫生长的刺激。基于这些发现，我们假设ERα共配体可以与MHT中使用的现有雌激素联合使用，以阻断E2的不良增殖作用，从而使ERα共配体/雌激素组合安全地用于长期MHT治疗。本I期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特征的领先ERα共配体/雌激素组合，然后将其推进II期提案中的药代动力学/药效学和其他临床前试验。这些研究有可能促进新型MHT的早期开发，可用于长期给药，以预防与绝经相关的慢性疾病，如骨质疏松症，肥胖症，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.