Journal
SCIENCE SIGNALING
Volume 9, Issue 429, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aad8170
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Funding
- Breast Cancer Research Foundation
- NIH from the National Center for Complementary and Integrative Health (NCCIH) [R37 DK015556, P50AT006268]
- Office of Dietary Supplements (ODS)
- National Cancer Institute (NCI)
- National Institute of Food and Agriculture, U.S. Department of Agriculture [ILLU-698-909]
- NIH [HL087564]
- Associates First Capital Corporation Distinguished Chair in Pediatrics at University of Texas (UT) Southwestern
- Sun Yat-sen University, China
- Division of Intramural Research, National Institute of Environmental Health Sciences [1ZIAES070065]
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There is great medical need for estrogens with favorable pharmacological profiles that support desirable activities for menopausal women, such as metabolic and vascular protection, but that lack stimulatory activities on the breast and uterus. We report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained pathway preferential estrogens (PaPEs), which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear PaPEs, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily.
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