# Development of reprogramming ligands for menopausal hormone therapy

> **NIH NIH R43** · IATERION, INC. · 2021 · $255,543

## Abstract

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.

## Key facts

- **NIH application ID:** 10255690
- **Project number:** 1R43AG072965-01
- **Recipient organization:** IATERION, INC.
- **Principal Investigator:** DALE C LEITMAN
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $255,543
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10255690

## Citation

> US National Institutes of Health, RePORTER application 10255690, Development of reprogramming ligands for menopausal hormone therapy (1R43AG072965-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10255690. Licensed CC0.

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