Cyclic Ketoximes as Estrogen Receptor β Selective Agonists

Carlotta Granchi, Margherita Lapillo, Concetta Russo Spena, Flavio Rizzolio, Tiziano Tuccinardi, Teresa A. Martin, Kathryn E. Carlson, John A. Katzenellenbogen, Filippo Minutolo

Research output: Contribution to journalArticlepeer-review

Abstract

The development of estrogen receptor β (ERβ)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ERα and ERβ, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ERβ. In this paper, further structural evolution of the salicylketoximes is presented: two of the newly synthesized five-membered cyclic ketoximes bind with nanomolar affinities to ERβ, and they show selectivity for this subtype over ERα. Their agonist character was confirmed by cell-free coactivator recruitment assays, in which we demonstrated the ability of these compounds to form an active complex with ERβ capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ERβ binding were rationalized by molecular-modeling studies.

Original languageEnglish (US)
Pages (from-to)1752-1761
Number of pages10
JournalChemMedChem
DOIs
StatePublished - 2016

Keywords

  • cancer
  • estrogen
  • ligand binding
  • oximes
  • receptors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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