Structure-based design of estrogen-related receptors modulators

Estrogen-related receptors (ERRs) are members of the nuclear hormone receptor (NR) superfamily. The ERR subfamily comprise three members, ERRα, ERRβ, and ERRγ. They are closely related to the estrogen receptors (ERα and ERβ), but unlike ER receptors, ERRs have constitutive activity and can function in the absence of ligands. The ERRs are orphan receptors because no natural ligands have been identified for any of the three ERR isoforms. Although ERRs are structurally related to ERs and share sequence similarity with these receptors, they do not bind with estrogens. ERRs are expressed mostly in all tissues that have been examined to date with variation of the level and type of isoform existed in a particular tissue. ERRs play an essential role in many physiological processes, and they are potential therapeutic targets in many disease areas such as Alzheimer's disease, cancer, diabetes, and other metabolic diseases. In this chapter, we mainly focus on the structure and function of ERRs, and the medicinal chemistry efforts to design modulators of these receptors. We put great emphasis on the structure-based design of ERR modulators, which we believe is an essential tool to advance the drug discovery in this particular research area.