Development of reprogramming ligands for menopausal hormone therapy

项目摘要/摘要 由于更年期女性的寿命越来越长，她们面临的健康问题正变得更加普遍。 公认的短期症状，如潮热、睡眠障碍和情绪波动会导致较低的 生活质量和工作效率的损失。更年期长期雌激素缺乏与 慢性病发病率增加，如骨质疏松症、肥胖、糖尿病、代谢综合征和 心血管疾病。更年期激素疗法(Mht)已被用于缓解短期绝经。 症状和预防一些慢性病。妇女健康倡议(WHI)发现，长期肥胖的风险 定期治疗超过了好处。在WHI结果公布后，MHT的使用率大幅下降 审判被报道过。它现在被批准用于治疗潮热和阴道症状，但不能用于慢性病 预防。MHT目前推荐短期使用5年。无数更年期女性 继续焦急地等待一个安全的长期MHT，以提高他们的生活质量和健康。有过的女性 超过5年的血管舒缩症状和低骨密度、骨质疏松症和糖尿病前期病史 从长期的MHT中受益匪浅。不幸的是，对于更年期女性来说， 制药公司将很快推出长期的MHT产品，这是他们长期追求的 雌激素激动剂和拮抗剂，与雌二醇(E2)结合口袋结合。在MHT之后近80年 这一战略显然不起作用，因为没有长期的MHT可用。我们决定 寻求一种不同的方法，筛选与E2协同作用的药物，而不是作为激动剂 或者是敌手。我们发现了一类名为雌激素受体α(ERα)重编程的化合物 重新编程E2对基因表达和细胞增殖的影响的Coligand。我们发现， 重新编程药物和E2的组合调节不被重新编程药物改变的基因 或者单独使用E2，证明了这种组合诱导了一组新的基因。可重新编程的Coligand 阻断了人类乳腺癌细胞的增殖和小鼠子宫的生长，以回应雌二醇。基座 根据这些发现，我们的目标是用重新编程的Coligand取代MHT中的孕激素成分 并将其添加到单独使用雌激素的配方中，以产生E2/Coligand组合。我们的假设是，一个 E2/Coligand组合将比目前单独使用雌激素和雌激素/孕激素MHT配方更安全 市场上针对的是短期的更年期症状，并可作为长期治疗，预防慢性 与更年期有关的情况。在这个提案中，我们将准备我们的原型的合成类比 重新编程Coligand，并确定与E2结合的最佳类似物，以便将来在动物模型和 临床发展所需的其他临床前研究。

Project Summary/Abstract Health issues facing menopausal women are becoming much more prevalent due to their increasing longevity. Well-recognized short-term symptoms, such as hot flashes, sleep disturbances and mood swings lead to lower quality of life and loss of work productivity. Prolonged estrogen deficiency during menopause is associated with an increased incidence of chronic diseases, such as osteoporosis, obesity, diabetes, metabolic syndrome and cardiovascular disease. Menopausal hormone therapy (MHT) has been used to alleviate short-term menopausal symptoms and prevent some chronic conditions. The Women’s Health Initiative (WHI) found that the risk of long- term treatment outweighed the benefits. The use of MHT has dropped dramatically after the results of the WHI trial were reported. It is now approved to treat hot flashes and vaginal symptoms, but not for chronic disease prevention. MHT is currently recommended for short-term use of 5 years. Countless menopausal women continue to wait anxiously for a safe long-term MHT to improve their quality of life and health. Women who have vasomotor symptoms beyond 5 years and a history of low bone density, osteoporosis, and prediabetes would greatly benefit from long-term MHT. Unfortunately for menopausal women it is unlikely that the major pharmaceutical companies will have a long-term MHT product soon based on their longstanding pursuit of estrogen agonists and antagonists, which bind to the estradiol (E2) binding pocket. Nearly 80 years after MHT was approved it is clear that this strategy is not working since no long-term MHT is available. We decided to pursue a different approach by screening drugs that act synergistically with E2 rather than acting as an agonist or antagonist. We discovered a class of compounds termed estrogen receptor alpha (ERα) reprogramming coligands that reprogram the effects of E2 on gene expression and cell proliferation. We found that the combination of the reprogramming drug and E2 regulates genes that are not altered by the reprogramming drug or E2 alone, demonstrating that the combination induces a new set of genes. The reprogramming coligand blocked the proliferation of human breast cancer cells and growth of the mouse uterus in response to E2. Based on these findings our objective is to replace the progestin component in MHT with a reprogramming coligand and add it to the estrogen-alone formulation to generate an E2/coligand combination. Our hypothesis is that an E2/coligand combination will be safer than the current estrogen-alone and estrogen/progestin MHT formulations on the market for short-term menopausal symptoms, and can be used as long-term therapy to prevent chronic conditions associated with menopause. In this proposal, we will prepare synthetic analogs of our prototype reprogramming coligand and identify the best analogs to combine with E2 for future testing in animal models and other preclinical studies required for clinical development.