Research ArticleDRUG DESIGN

Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues

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Science Signaling  24 May 2016:
Vol. 9, Issue 429, pp. ra53
DOI: 10.1126/scisignal.aad8170

Designing better estrogens

Estrogen and synthetic versions can enhance the repair of blood vessels after injury or improve metabolism in the liver and adipose tissue, but they can also cause breast or uterine cancer, because they stimulate cell proliferation in these reproductive tissues. Madak-Erdogan et al. designed estrogen-like molecules that had reduced receptor affinity and that did not enhance ductal mammary gland branching (a sign of mammary gland growth) or increase uterine weight in ovariectomized mice. These estrogens provided vascular and metabolic benefits and thus could be further developed as postmenopausal hormone replacement therapies.


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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