In search of novel drug target sites on estrogen receptors using RNA aptamers.

Estrogen receptor α (ERα) is a well-validated drug target for a majority of breast cancers. But the target sites on this receptor are far from exhaustively defined. Almost all ER antagonists in clinical use function by binding to the ligand-binding pocket to occlude agonist access. Resistance to this type of drugs may develop over time, not caused by the change of ERα itself, but by changes in ER associated proteins. This observation is fueling the development of reagents that downregulate ER activity through novel binding sites. However, it is challenging to find general ER antagonists that act independently from other known ER ligands. In this report, we describe the utility of RNA aptamers in the search for new drug target sites on ERα. We have identified three high affinity aptamers and characterized one of them in detail. This aptamer interacted with ERα in a way not affected by the presence or absence of either the steroidal ligands or the estrogen response DNA elements, and effectively inhibited ER-mediated transcriptional activation in a breast cancer cell line. Serving as a novel drug lead, it may also be used to guide the rational chemical synthesis of small molecule drugs or to perform screens of small molecule libraries for those that are able to displace the aptamer from its binding site.