Estrogen receptor beta (ER beta) 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 a and beta are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ER beta 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 ER beta-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.

Highly Selective Salicylketoxime-Based Estrogen Receptor beta Agonists Display Antiproliferative Activities in a Glioma Model

RIZZOLIO, Flavio;
2015-01-01

Abstract

Estrogen receptor beta (ER beta) 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 a and beta are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ER beta 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 ER beta-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.
2015
58
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10278/3683000
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