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Development of Pathway Preferential Estrogens Affording Beneficial Metabolic and Vascular Actions without Reproductive Tissue Stimulation in Mice


ABSTRACT: There is great medical need for estrogens having favorable pharmacological profiles, supporting desirable activities for menopausal women such as metabolic and vascular protection but lacking stimulatory activities on the breast or uterus. Here, we report the development of structurally novel estrogens with favorable target tissue-selective estrogenic activity. Through a process of structural alteration of the hormone estradiol that preserves essential chemical and physical features of estradiol but greatly moderates its binding affinity for the estrogen receptors (ERs), we obtained Pathway Preferential Estrogens (PaPEs) capable of having interaction with ER that is sufficient to activate the extranuclear-initiated signaling pathway preferentially over the direct nuclear-initiated pathway. PaPE modulate a pattern of gene regulation and cellular and biological processes that result in essentially no stimulation of reproductive and mammary tissues and breast cancer cells, but have a favorable pattern of activity on metabolic tissues and the vasculature. The structural permutation process represents a novel approach to govern the balance in utilization of extranuclear vs. nuclear pathways of ER action to obtain tissue-selective/non-nuclear pathway-preferential estrogens, which should prove to be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily. 24 samples; inhibitor and time course experiments

ORGANISM(S): Homo sapiens

SUBMITTER: Zeynep Madak Erdogan 

PROVIDER: E-GEOD-73663 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Madak-Erdogan Zeynep Z   Kim Sung Hoon SH   Gong Ping P   Zhao Yiru C YC   Zhang Hui H   Chambliss Ken L KL   Carlson Kathryn E KE   Mayne Christopher G CG   Shaul Philip W PW   Korach Kenneth S KS   Katzenellenbogen John A JA   Katzenellenbogen Benita S BS  

Science signaling 20160524 429


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  ...[more]

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