A New Series of Estrogen Receptor Modulators That Display Selectivity for Estrogen Receptor β

Henke, Brad R.; Consler, Thomas G.; Go, Ning; Hale, Ron; Hohman, Dana R; Jones, Stacey A.; Lu, Amy T.; Moore, Linda B.; Moore, John T.; Orband‐Miller, Lisa A.; Robinett, R. Graham; Shearin, Jean; Spearing, Paul K.; Stewart, Eugene L.; Turnbull, Philip; Weaver, Susan E.; Williams, Shawn P.; Wisely, G. Bruce; Lambert, Millard H.

doi:10.1021/jm020291h

Cited by 155 publications

(92 citation statements)

References 53 publications

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“…A new generation of antiestrogenic compounds and selective ER modulators (SERM) are in development, some of which preferentially target ERb. [38][39][40] As yet, none of these SERM has been tested in angiosarcomas and it remains uncertain whether the effect on normal endothelial cells would preclude systemic therapy. Nonetheless, further study is warranted.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

et al. 2004

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The importance of estrogen in vascular neoplasia is suggested by a predilection for women and a tendency for rapid growth during pregnancy. Although early experiments using radioligand assays demonstrated estrogen receptor (ER) expression, these findings were not confirmed by subsequent immunohistochemical studies which were performed with antibodies raised against ERa. A newly discovered estrogen receptor subtype, ERb, has not been previously characterized in vascular lesions. In order to verify the expression of estrogen receptors in vascular neoplasms as well as to clarify the inconsistency between radioligand and early immunohistochemical studies, we examined a series of 53 benign and malignant vascular neoplasms for ERb expression. All of the subtypes of vascular neoplasia examined had nuclear expression of ERb. The majority of cases (94%) displayed 2 þ to 3 þ staining. The discrepancy between radioligand studies and previous immunohistochemical studies is attributable to the use of antibodies raised against ERa, which is not expressed in vascular lesions, and not ERb, which is broadly expressed in both benign and malignant vascular neoplasms. Although ERb may be of limited diagnostic use in vascular neoplasia due to its broad expression, the potential exists for a therapeutic approach using ER agonists. The role of estrogen in vascular neoplasia has long been suspected due to the observation that vascular neoplasms tend to grow rapidly during pregnancy and in adolescence. 1 These clinical observations were initially substantiated by early experiments in the 1980s using radioligand assays, which confirmed the presence of the estrogen receptor (ER) in vascular tumors; 2,3 however, with the advent of immunohistochemical techniques, subsequent studies performed in the 1990s with antibodies raised against the ER refuted these earlier data and it appeared that the newer technology had exposed the limitations of the older biochemical assays. [4][5][6][7] Recently, an additional ER subtype, estrogen receptor beta (ERb), 8 was identified and the previous ER against which the original antibodies were raised was renamed estrogen receptor alpha (ERa). Although ERa has been assessed immunohistochemically in vascular neoplasms and found to be absent, ERb has not been previously characterized in these entities. In order to verify the expression of ER in vascular tumors as well as to clarify the inconsistency between radioligand and early immunohistochemical studies, we examined a series of 53 benign and malignant vascular neoplasms for ERb expression. Materials and methodsIn all, 22 cases of angiosarcoma, three cases of Kaposi sarcoma, one case of epithelioid hemangioendothelioma, two cases of spindle-cell hemangioma, four cases of infantile hemangioendothelioma, 13 cases of hemangioma, seven cases of lymphangioma and one case of papillary endothelial hyperplasia were identified and retrieved from the paraffin archives of the University of Chicago. Formalin-fixed paraffin-embedded specimens were cut into 4-mm sections an...

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

et al. 2004

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“…(15 (16 (19). The product was obtained as a white solid, 0.67 g (82.0%) yield; mp: 132-134 °C; IR (KBr): 3571-2853 (br, OH, acid), 3316 (NH, amine), 1721 (CO, acid) cm (20). The product was obtained as a white solid, 0.54 g (71.8%) yield; mp:158-161 °C; IR (KBr): 3614-2855 (br, OH, acid), 3320 (NH, amine) 1721 (CO, acid) cm The mixture of 2,4-dichloro-6-morpholino-1,3,5-triazine 12 (0.47 g, 2 mmol) and triethyl amine (0.42 mL, 3 mmol) in 1,4-dioxane (5 mL) was stirred at room temperature until a white suspension was formed.…”

Section: General Procedures For the Synthesis Of N-(46-dipiperidino-1mentioning

confidence: 99%

“…These compounds are known to be VLA-4 integrin antagonists, anti-inflammatory agents [18], sorbitol dehydrogenase inhibitors [19], estrogen receptor modulators [20], potential anti-trypanosomal drugs [21], antimalarial agents [22][23][24][25][26][27][28][29], hypolipidemic agents, [30] and antimicrobial agents [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Preliminary Biological Evaluation of 1,3,5-Triazine Amino Acid Derivatives to Study Their MAO Inhibitors

et al. 2015

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Three series of 4,6-dimethoxy-, 4,6-dipiperidino-and 4,6-dimorpholino-1,3,5-triazin-2-yl) amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 7, 18, and 25 had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity.

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“…While both receptors bind estradiol and activate transcription through an ERE, they exert differential transcriptional actvities through AP-1 sites, pointing to differential gene regulation through these closely related receptors. In this field, recent progress in pharmaco-development has yielded the identification of selective ERb-agonistic agents, adding yet further complexity to the modulation of ER-regulated transcription (72 …”

Section: Identification Of a Novel Estrogen Receptor Erbmentioning

confidence: 99%

Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer

Hanstein

Djahansouzi²,

Dall³

et al. 2004

European Journal of Endocrinology

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Evidence for a role of ovarian factors in the growth of metastatic breast cancer was first recognized over 100 years ago. Today, anti-estrogens are central to the treatment of breast cancer of all stages. We now understand that the action of estrogen is mediated by the estrogen receptors (ER) which are members of the nuclear receptor family of ligand-regulated transcription factors. In this article we review the molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects. We discuss possible mechanisms of failure of treatment with current anti-estrogens and how newer anti-estrogens under development attempt to address these problems. In addition an expanded view of the molecular mechanisms of estrogen action is leading to the development of novel selective ER modulators or SERMs.European Journal of Endocrinology 150 243-255

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A New Series of Estrogen Receptor Modulators That Display Selectivity for Estrogen Receptor β

Cited by 155 publications

References 53 publications

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

Synthesis and Preliminary Biological Evaluation of 1,3,5-Triazine Amino Acid Derivatives to Study Their MAO Inhibitors

Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer

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