Novel Anticancer Agents that Block Dissociation of Hsp90 from Estrogen Receptors in Breast Cancers.

摘要

Heat shock protein 90 (Hsp90) is a chaparone protein that facilitates the folding of estrogen receptors (ERs) and other proteins involved in breast cancer proliferation. This protein is under investigation as a target of anticancer drugs because breast cancer cells contain Hsp90 in an activated high affinity conformation that is particularly susceptible to Hsp90 inhibitors. These inhibitors include the anticancer agent geldanamycin (GDM), which is thought to inhibit the proliferation of cancer cells in part by blocking agonist-induced release of steroid hormone receptors such as ERs from Hsp90. To further stabilize this interaction, we synthesized estrogen receptor ligands coupled to GDM to enforce heterodimerization of ER and Hsp90 in mammalian cells. We demonstrated that at a concentration of 10 micromolar, an estrone (E1)-GDM chimera can heterodimerize recombinant ER and Hsp90 proteins in vitro. Moreover, competition experiments established that this compound stabilizes interactions between ERs and Hsp90 in human cells. These studies demonstrated that bifunctional small molecules can affect ERs by heterodimerization with Hsp90, providing a new strategy for inhibiting ERs involved in breast cancer proliferation.