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

Zeynep Madak-Erdogan, Sung Hoon Kim, Ping Gong, Yiru C. Zhao, Hui Zhang, Ken L. Chambliss, Kathryn E. Carlson, Christopher G. Mayne, Philip W. Shaul, Kenneth S. Korach, John A. Katzenellenbogen, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberra53
JournalScience Signaling
Volume9
Issue number429
DOIs
StatePublished - May 24 2016

Fingerprint

Blood Vessels
Estrogens
Tissue
Ligands
Estrogen Receptors
Adipose Tissue
Breast Neoplasms
Biological Phenomena
Cytoplasmic and Nuclear Receptors
Gene expression
Liver
Weight Gain
Uterus
Breast
Repair
Fats
Cells
Body Weight
Hormones
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Madak-Erdogan, Z., Kim, S. H., Gong, P., Zhao, Y. C., Zhang, H., Chambliss, K. L., ... Katzenellenbogen, B. S. (2016). Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. Science Signaling, 9(429), [ra53]. https://doi.org/10.1126/scisignal.aad8170

Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. / Madak-Erdogan, Zeynep; Kim, Sung Hoon; Gong, Ping; Zhao, Yiru C.; Zhang, Hui; Chambliss, Ken L.; Carlson, Kathryn E.; Mayne, Christopher G.; Shaul, Philip W.; Korach, Kenneth S.; Katzenellenbogen, John A.; Katzenellenbogen, Benita S.

In: Science Signaling, Vol. 9, No. 429, ra53, 24.05.2016.

Research output: Contribution to journalArticle

Madak-Erdogan, Z, Kim, SH, Gong, P, Zhao, YC, Zhang, H, Chambliss, KL, Carlson, KE, Mayne, CG, Shaul, PW, Korach, KS, Katzenellenbogen, JA & Katzenellenbogen, BS 2016, 'Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues', Science Signaling, vol. 9, no. 429, ra53. https://doi.org/10.1126/scisignal.aad8170
Madak-Erdogan, Zeynep ; Kim, Sung Hoon ; Gong, Ping ; Zhao, Yiru C. ; Zhang, Hui ; Chambliss, Ken L. ; Carlson, Kathryn E. ; Mayne, Christopher G. ; Shaul, Philip W. ; Korach, Kenneth S. ; Katzenellenbogen, John A. ; Katzenellenbogen, Benita S. / Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. In: Science Signaling. 2016 ; Vol. 9, No. 429.
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