Estrogen receptor reprogramming ligands for the prevention of protracted menopausal symptoms and chronic diseases

雌激素受体重编程配体用于预防长期更年期症状和慢性疾病

• 批准号: 10759566
• 负责人: DALE C LEITMAN
• 金额: $ 29.89万
• 依托单位: IATERION, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10759566
• 关键词: Adverse effects; Affect; Allosteric Site; Animal Model; Atrophic; Award; Benefits and Risks; Binding; Biological Assay; Biological Markers; Blood coagulation; Bone Density; Breast; Breast Cancer Cell; Breast Cancer Risk Factor; Cardiovascular Diseases; Cells; Chemosensitization; Chronic; Chronic Disease; Clinical; Clinical Trials; Complex; Data; Development; Diabetes Mellitus; Dose; Drops; Effectiveness; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogen deficiency; Estrogens; Fatty acid glycerol esters; Formulation; Fright; Future; Gene Expression; Genes; Genitourinary system; Goals; Growth; Health; Health Care Costs; High Fat Diet; Hot flushes; Human; Incidence; Lead; Legal patent; Ligands; Link; Longevity; MCF7 cell; Marketing; Measures; Mediating; Menopausal Symptom; Menopause; Metabolic syndrome; Metabolism; Modeling; Molecular Conformation; Moods; Morbidity - disease rate; Mus; Natural Compound; Night Sweating; Obesity; Organ; Osteoporosis; Ovariectomy; Pathway interactions; Pharmaceutical Preparations; Phase; Postmenopause; Prediabetes syndrome; Preparation; Prevention; Primary Prevention; Productivity; Progesterone; Progestins; Proliferating; Property; Publications; Quality of life; Recommendation; Regimen; Risk; Safety; Selective Estrogen Receptor Modulators; Serum; Skin Temperature; Sleep; Small Business Innovation Research Grant; Symptoms; Tail; Testing; Therapeutic Uses; Time; Toxic effect; Uterus; Vagina; Woman; Women' s Health; Work; Xenograft procedure; analog; anxious; bone; bone turnover; clinical development; drug candidate; experience; experimental study; gene product; improved; lead candidate; malignant breast neoplasm; menopausal hormone therapy; mortality; mouse model; neoplastic cell; new chemical entity; pharmacologic; prevent; response; side effect; tumor

Project Summary/Abstract Because of longer lifespans, health problems affecting menopausal women are becoming increasingly common. Hot flashes, sleep issues, and mood swings are typical short-term symptoms that can have a negative impact on quality of life and productivity at work. An increased incidence of chronic disorders such as osteoporosis, obesity, diabetes, metabolic syndrome, and cardiovascular disease is linked to long-term estrogen insufficiency following menopause. Menopausal hormone therapy (MHT) is effective at reducing menopausal symptoms and preventing some chronic diseases, but according to the Women's Health Initiative (WHI), long-term therapy has more risks than benefits. The use of MHT among menopausal women has sharply dropped since the publication of the WHI data. MHT is currently recommended for a 5-year short-term treatment of hot flashes and vaginal symptoms. MHT is no longer recommended for the primary prevention of chronic diseases. Countless menopausal women continue to wait anxiously for a safer long-term MHT to improve their quality of life and health. In the meantime, many women opt for unproven supplements to relieve menopausal symptoms. There is a significant unmet need for developing new MHT formulations that can be utilized for long-term therapy because many women suffer from menopausal symptoms for more than five years and chronic diseases increase throughout menopause. Almost 80 years after MHT was approved, there is still no MHT formula safe for long- term therapy. Our objective is to develop a safer MHT formula that can be used long-term to treat protracted menopausal symptoms and prevent chronic diseases, such as osteoporosis, diabetes, obesity, and metabolic syndrome. We discovered a class of compounds that we termed estrogen receptor (ER) reprogramming ligands. We found that when a reprogramming ligand is combined with estradiol (E2), a new set of genes are regulated that are not regulated by the reprogramming ligand or E2 alone. The reprogramming ligand blocked the proliferation of human breast cancer cells and the growth of the mouse uterus in response to E2. Our goal is to create an E2/reprogramming ligand combination by replacing the progestin component of MHT with a reprogramming ligand and adding it to the estrogen-alone formulation. Our hypothesis is that the E2/reprogramming ligand combination will be safer than the single estrogen and estrogen/progestin MHT preparations currently on the market so that they can be used as a long-term therapy to prevent protracted menopausal symptoms and chronic diseases. Our original reprogramming ligand was a natural compound. To improve its pharmacological properties and strengthen its patent protection, we prepared and identified several synthetic analogs that behave similarly to the natural reprogramming ligand in cell-based assays. As the next step in the clinical development pathway, we will test the synthetic analogs in animal models to select the lead analog that is the most effective and safe for future clinical trials.

项目摘要/摘要 由于寿命更长，影响更年期妇女的健康问题变得越来越普遍。 潮热，睡眠问题和情绪波动是典型的短期症状，可能会产生负面影响 关于工作中的生活质量和生产力。慢性疾病（例如骨质疏松症）的发生率增加， 肥胖，糖尿病，代谢综合征和心血管疾病与长期雌激素不足有关 在更年期之后。更年期激素疗法（MHT）可有效减少更年期症状和 防止某些慢性疾病，但根据妇女健康倡议（WHI），长期治疗已有 风险多于利益。自出版以来，在更年期妇女中使用MHT已大幅下降 whi数据。目前，建议使用MHT进行5年短期治疗热闪光和阴道 症状。不再建议使用MHT用于初级预防慢性疾病。无数 更年期妇女继续焦急地等待更安全的长期MHT，以改善其生活质量，并 健康。同时，许多女性选择未经证实的补充剂来缓解更年期症状。那里 是开发可用于长期治疗的新型MHT配方的重要需求 因为许多女性患有绝经症状超过五年，并且慢性疾病增加 整个更年期。 MHT批准后将近80年，仍然没有MHT公式可安全。 术语治疗。我们的目标是开发一个可长期使用的更安全的MHT公式 更年期症状并预防慢性疾病，例如骨质疏松症，糖尿病，肥胖和代谢 综合征。我们发现了一类称为雌激素受体（ER）重编程配体的化合物。 我们发现，当重编程配体与雌二醇（E2）结合时，调节了一组新的基因 仅由重新编程的配体或E2调节。重编程配体阻止了 人类乳腺癌细胞的增殖和小鼠子宫的生长响应E2。我们的目标是 通过用A替换MHT的孕激素成分来创建E2/重编程配体组合 重新编程配体并将其添加到雌激素的配方中。我们的假设是 E2/重编程配体组合将比单雌激素和雌激素/孕激素MHT更安全 目前在市场上的准备工作，以便可以用作防止持久的长期治疗 更年期症状和慢性疾病。我们最初的重编程配体是天然化合物。到 提高其药理特性并增强其专利保护，我们准备并确定了几个 与基于细胞的测定中的自然重编程配体相似的合成类似物。下一个 在临床开发途径中步骤，我们将测试动物模型中的合成类似物以选择铅 对于将来的临床试验，最有效，最安全的模拟。