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 lowerquality of life and loss of work productivity. Prolonged estrogen deficiency during menopause is associated withan increased incidence of chronic diseases, such as osteoporosis, obesity, diabetes, metabolic syndrome andcardiovascular disease. Menopausal hormone therapy (MHT) has been used to alleviate short-term menopausalsymptoms 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 WHItrial were reported. It is now approved to treat hot flashes and vaginal symptoms, but not for chronic diseaseprevention. MHT is currently recommended for short-term use of 5 years. Countless menopausal womencontinue to wait anxiously for a safe long-term MHT to improve their quality of life and health. Women who havevasomotor symptoms beyond 5 years and a history of low bone density, osteoporosis, and prediabetes wouldgreatly benefit from long-term MHT. Unfortunately for menopausal women it is unlikely that the majorpharmaceutical companies will have a long-term MHT product soon based on their longstanding pursuit ofestrogen agonists and antagonists, which bind to the estradiol (E2) binding pocket. Nearly 80 years after MHTwas approved it is clear that this strategy is not working since no long-term MHT is available. We decided topursue a different approach by screening drugs that act synergistically with E2 rather than acting as an agonistor antagonist. We discovered a class of compounds termed estrogen receptor alpha (ERα) reprogrammingcoligands that reprogram the effects of E2 on gene expression and cell proliferation. We found that thecombination of the reprogramming drug and E2 regulates genes that are not altered by the reprogramming drugor E2 alone, demonstrating that the combination induces a new set of genes. The reprogramming coligandblocked the proliferation of human breast cancer cells and growth of the mouse uterus in response to E2. Basedon these findings our objective is to replace the progestin component in MHT with a reprogramming coligandand add it to the estrogen-alone formulation to generate an E2/coligand combination. Our hypothesis is that anE2/coligand combination will be safer than the current estrogen-alone and estrogen/progestin MHT formulationson the market for short-term menopausal symptoms, and can be used as long-term therapy to prevent chronicconditions associated with menopause. In this proposal, we will prepare synthetic analogs of our prototypereprogramming coligand and identify the best analogs to combine with E2 for future testing in animal models andother preclinical studies required for clinical development. Project Narrative Estrogens in menopausal hormone therapy (MHT) can prevent some long-term conditions that occur in postmenopausal women. Current MHT regimens are not approved for long-term treatment because it produces major adverse effects. The objective of this proposal is to develop a safer MHT regimen that can be used for long-term therapy to prevent menopausal symptoms and diseases associated with menopause. 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