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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Paterni, I., Bertini, S., Granchi, C., Tuccinardi, T., Macchia, M., Martinelli, A., Caligiuri, I., Toffoli, G., Rizzolio, F., Carlson, K. E., Katzenellenbogen, B. S., Katzenellenbogen, J. 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