Novel Strategies for the Identification and Characterization of Selective Estrogen Receptor Modulators (SERMs)

摘要

Estrogens promote growth of breast and endometrial cancers. Selective estrogen receptor modulators (SERMs) block the activity of estrogen in selective tissues and control the growth of these cancers while avoiding many unwanted side effects associated with the use of antiestrogens. The goal of our work is to identify mechanisms regulating the activity of SERMs and to develop strategies for the identification of novel SERMs. SERMs exert their activities by binding to the two estrogen receptors, ERalpha and ERbeta. while the characterization of ligand-bound ERs by X-ray crystallography gave many insights into ligand binding, they do not provide a coherent explanation for the tissue- and receptor isotype-specific activities displayed by many ligands. Our results indicate that the F-domain, a C-terminal extension of the ligand binding domain (LED) regulates ligand and coregulator binding in a receptor- specific manner. Moreover, SERMs might differ from pure agonists or antagonists in terms of the dynamics rather than the nature of the ligand-induced structural changes. We have constructed a series of fluorescent ER LED derivatives that will not only give novel insights into the actions of SERMs but also provide a powerful strategy for the identification of novel SERMs for breast cancer therapy.