Development of reprogramming ligands for menopausal hormone therapy

用于更年期激素治疗的重编程配体的开发

基本信息

批准号：
10255690
负责人：
DALE C LEITMAN
金额：
$ 25.55万
依托单位：
IATERION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255690
关键词：
Adverse effects Agonist Allosteric Site Animal Model Animals Atrophic Binding Biological Biological Assay Biological Availability Bone Density Breast Breast Cancer Cell Breast Cancer Risk Factor Cancer Cell Growth Cardiovascular Diseases Cell Proliferation Cells Chalcones Chronic Chronic Disease Complex Development Diabetes Mellitus Disease Dose Drops Drug Screening Edible Plants Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Formulation Fright Future Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genitourinary system Health Health Care Costs Hot flushes Human Incidence Lead Length Ligands Longevity MCF7 cell Menopausal Symptom Menopause Metabolic syndrome Metabolism Molecular Molecular Conformation Moods Morbidity - disease rate Mus Night Sweating Obesity Osteoporosis Pharmaceutical Preparations Pharmacologic Substance Pharmacology Postmenopause Prediabetes syndrome Prevention Productivity Progestins Property Quality of life Recording of previous events Regimen Reporting Risk Safety Selective Estrogen Receptor Modulators Sleep disturbances Symptoms Testing Transfection Uterus Vagina Vasomotor Woman Women&apos s Health Work analog anxious base bone turnover clinical development commercialization disorder prevention drug candidate drug development experience gene product hormone therapy improved lead candidate mortality novel drug class pill preclinical study prevent prototype response scaffold side effect transcriptome sequencing water solubility

项目摘要

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.

项目概要/摘要由于寿命的延长，更年期妇女面临的健康问题变得更加普遍。众所周知的短期症状，如潮热、睡眠障碍和情绪波动会导致较低的睡眠质量。更年期期间长期雌激素缺乏与生活质量和工作效率下降有关。慢性病的发病率增加，如骨质疏松症、肥胖症、糖尿病、代谢综合征和心血管疾病。更年期激素疗法（MHT）已被用来缓解短期更年期症状。女性健康倡议 (WHI) 发现长期患病的风险。 WHI 结果公布后，长期治疗超过了 MHT 的使用量。据报道，该药物现已被批准用于治疗潮热和阴道症状，但不适用于治疗慢性疾病。目前推荐无数更年期妇女短期使用MHT。继续焦急地等待安全的长期 MHT 来改善她们的生活质量和健康。超过 5 年的血管舒缩症状以及低骨密度、骨质疏松症和糖尿病前期病史不幸的是，对于更年期女性来说，长期 MHT 不太可能带来很大的好处。制药公司基于长期以来的追求，很快就会有一个长期的MHT产品。雌激素激动剂和拮抗剂，在 MHT 近 80 年后与雌二醇 (E2) 结合袋结合。获得批准后，很明显该策略不起作用，因为没有长期 MHT 可用。通过筛选与 E2 协同作用而不是作为激动剂的药物来寻求不同的方法我们发现了一类称为雌激素受体α（ERα）重编程的化合物。我们发现，重编程 E2 对基因表达和细胞增殖的影响的共配体。重编程药物和 E2 的组合可调节不受重编程药物影响的基因或单独的E2，证明该组合诱导了一组新的基因重编程共配体。基于 E2 的反应可阻断人类乳腺癌细胞的增殖和小鼠子宫的生长。根据这些发现，我们的目标是用重编程共配体取代 MHT 中的孕激素成分并将其添加到单独的雌激素制剂中以产生 E2/共配体组合。 E2/共配体组合将比目前的单独雌激素和雌激素/孕激素 MHT 制剂更安全市场上用于治疗短期更年期症状，并可作为预防慢性更年期症状的长期疗法在本提案中，我们将制备原型的合成类似物。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中进行测试临床开发所需的其他临床前研究。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

2',3',4'-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism.

DOI：
10.1186/s10020-022-00470-z
发表时间：
2022-04-25
期刊：
MOLECULAR MEDICINE
影响因子：
5.7
作者：
Herber, Candice B.;Yuan, Chaoshen;Chang, Anthony;Wang, Jen-Chywan;Cohen, Isaac;Leitman, Dale C.
通讯作者：
Leitman, Dale C.