Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model

Ilaria Paterni, Simone Bertini, Carlotta Granchi, Tiziano Tuccinardi, Marco Macchia, Adriano Martinelli, Isabella Caligiuri, Giuseppe Toffoli, Flavio Rizzolio, Kathryn E. Carlson, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Filippo Minutolo

Research output: Contribution to journalArticle

Abstract

Estrogen receptor β (ERβ) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes α and β are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ERβ selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ERβ-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease.

Original languageEnglish (US)
Pages (from-to)1184-1194
Number of pages11
JournalJournal of Medicinal Chemistry
Volume58
Issue number3
DOIs
StatePublished - Feb 12 2015

Fingerprint

Glioma
Estrogen Receptors
Estrogens
Heterografts
Pharmacology
Ligands
Gene Expression
Cell Line
Neoplasms
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Paterni, I., Bertini, S., Granchi, C., Tuccinardi, T., Macchia, M., Martinelli, A., ... Minutolo, F. (2015). Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model. Journal of Medicinal Chemistry, 58(3), 1184-1194. https://doi.org/10.1021/jm501829f

Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model. / Paterni, Ilaria; Bertini, Simone; Granchi, Carlotta; Tuccinardi, Tiziano; Macchia, Marco; Martinelli, Adriano; Caligiuri, Isabella; Toffoli, Giuseppe; Rizzolio, Flavio; Carlson, Kathryn E.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.; Minutolo, Filippo.

In: Journal of Medicinal Chemistry, Vol. 58, No. 3, 12.02.2015, p. 1184-1194.

Research output: Contribution to journalArticle

Paterni, I, Bertini, S, Granchi, C, Tuccinardi, T, Macchia, M, Martinelli, A, Caligiuri, I, Toffoli, G, Rizzolio, F, Carlson, KE, Katzenellenbogen, BS, Katzenellenbogen, JA & Minutolo, F 2015, 'Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model', Journal of Medicinal Chemistry, vol. 58, no. 3, pp. 1184-1194. https://doi.org/10.1021/jm501829f
Paterni, Ilaria ; Bertini, Simone ; Granchi, Carlotta ; Tuccinardi, Tiziano ; Macchia, Marco ; Martinelli, Adriano ; Caligiuri, Isabella ; Toffoli, Giuseppe ; Rizzolio, Flavio ; Carlson, Kathryn E. ; Katzenellenbogen, Benita S. ; Katzenellenbogen, John A. ; Minutolo, Filippo. / Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 3. pp. 1184-1194.
@article{131fcc0dec4047449476a8eab840e1ac,
title = "Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model",
abstract = "Estrogen receptor β (ERβ) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes α and β are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ERβ selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ERβ-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease.",
author = "Ilaria Paterni and Simone Bertini and Carlotta Granchi and Tiziano Tuccinardi and Marco Macchia and Adriano Martinelli and Isabella Caligiuri and Giuseppe Toffoli and Flavio Rizzolio and Carlson, {Kathryn E.} and Katzenellenbogen, {Benita S.} and Katzenellenbogen, {John A.} and Filippo Minutolo",
year = "2015",
month = "2",
day = "12",
doi = "10.1021/jm501829f",
language = "English (US)",
volume = "58",
pages = "1184--1194",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Highly selective salicylketoxime-based estrogen receptor β agonists display antiproliferative activities in a glioma model

AU - Paterni, Ilaria

AU - Bertini, Simone

AU - Granchi, Carlotta

AU - Tuccinardi, Tiziano

AU - Macchia, Marco

AU - Martinelli, Adriano

AU - Caligiuri, Isabella

AU - Toffoli, Giuseppe

AU - Rizzolio, Flavio

AU - Carlson, Kathryn E.

AU - Katzenellenbogen, Benita S.

AU - Katzenellenbogen, John A.

AU - Minutolo, Filippo

PY - 2015/2/12

Y1 - 2015/2/12

N2 - Estrogen receptor β (ERβ) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes α and β are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ERβ selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ERβ-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease.

AB - Estrogen receptor β (ERβ) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes α and β are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ERβ selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ERβ-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease.

UR - http://www.scopus.com/inward/record.url?scp=84922830995&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922830995&partnerID=8YFLogxK

U2 - 10.1021/jm501829f

DO - 10.1021/jm501829f

M3 - Article

C2 - 25559213

AN - SCOPUS:84922830995

VL - 58

SP - 1184

EP - 1194

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -