TY - JOUR
T1 - Cyclic Ketoximes as Estrogen Receptor β Selective Agonists
AU - Granchi, Carlotta
AU - Lapillo, Margherita
AU - Spena, Concetta Russo
AU - Rizzolio, Flavio
AU - Tuccinardi, Tiziano
AU - Martin, Teresa A.
AU - Carlson, Kathryn E.
AU - Katzenellenbogen, John A.
AU - Minutolo, Filippo
PY - 2016/8/19
Y1 - 2016/8/19
N2 - 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.
AB - 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.
KW - cancer
KW - estrogen
KW - ligand binding
KW - oximes
KW - receptors
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U2 - 10.1002/cmdc.201600140
DO - 10.1002/cmdc.201600140
M3 - Article
C2 - 27135651
AN - SCOPUS:84983350464
SP - 1752
EP - 1761
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
ER -