Cyclic Ketoximes as Estrogen Receptor β Selective Agonists. (2nd May 2016)

• Record Type: Journal Article
• Authors: Granchi, Carlotta; Lapillo, Margherita; Spena, Concetta Russo; Rizzolio, Flavio; Tuccinardi, Tiziano; Martin, Teresa A.; Carlson, Kathryn E.; Katzenellenbogen, John A.; Minutolo, Filippo
• Is Part Of: ChemMedChem. Volume 11:Number 16(2016)
• Page Start: 1752
• Page End: 1761
• Publication Date: 2016-05-02
• Subjects: cancer -- estrogen -- ligand binding -- oximes -- receptors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600140
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : What a nice cycle tour ! A new class of ERβ‐selective agonists was developed by introducing a cyclic portion in the salicylketoxime scaffold. This structural modification gives rise to potent and selective ligands for ERβ. Cell‐free coactivator binding and recruitment assays prove that ERβ is able to recruit co‐regulator proteins upon ligand activation, which confirms the agonist functional properties of these compounds.