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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结/文摘