The development of estrogen receptor (ER)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ER and ER, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ER. 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 ER, and they show selectivity for this subtype over ER. 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 ER capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ER binding were rationalized by molecular-modeling studies.

Cyclic Ketoximes as Estrogen Receptor Selective Agonists

RIZZOLIO, Flavio;
2016

Abstract

The development of estrogen receptor (ER)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ER and ER, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ER. 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 ER, and they show selectivity for this subtype over ER. 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 ER capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ER binding were rationalized by molecular-modeling studies.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10278/3682988
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