title: Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues.
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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Madak-Erdogan
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Yiru C
authors.initials: YC
authors.lastname: Zhao
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA.
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. katzenel@illinois.edu.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D014599:Uterus / Q000187:drug effects
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen