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.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Paterni
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Isabella
authors.initials: I
authors.lastname: Caligiuri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
authors.forename: Flavio
authors.initials: F
authors.lastname: Rizzolio
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D047629:Estrogen Receptor beta; D010091:Oximes