Abstract 1858: Estrogen receptor beta as a tractable therapeutic target

Abstract

Abstract Nuclear receptors (NRs) regulate a variety of biological processes and are critically important in the emergence, prevention, and treatment of cancers. Many NRs represent well-validated drug targets as their ligands are used extensively in medicine. However, there still remains an active search for novel agonists and antagonists with enhanced selectivity. Estrogen receptor β (ERβ) is an attractive target for drug development. It plays different roles in gene expression from ERα, implicated in breast and uterine cancers, and displays overlapping but distinctive tissue distributions from ERα and non-redundant roles. Further, emerging evidence indicates that ERβ plays anti-proliferative and anti-apoptotic roles in a variety of cancers. These considerations have led to the suggestion that ERβ is an appealing tractable target for development of selective agonists to treat and prevent colon, breast, prostate, lung, and skin cancer and natural and synthetic estrogens for ERβ are being studied in colon, breast, and lung cancers. However, because of the high sequence similarities between ERα and ERβ, preferentially targeting one subtype can prove challenging. Repositioning of existing approved drugs with known side effect profiles can provide advantages because de novo drug design suffers from high developmental failure rates and undesirable side effects which have dramatically increased costs. Our research strategy is to identify and develop an ERβ agonist lead compound by using a systematic step-wise hit-to-lead campaign. We have identified a series of ERβ-selective lead compounds derived from screening libraries of clinically relevant compounds and have shown that some of these compounds display interesting and desirable selective modulator activities. Citation Format: Carly S. Filgueira, Cindy Benod, Xiaohua Lou, Anders Strom, Jan-Åke Gustafsson, Anders Berkenstam, Paul Webb. Estrogen receptor beta as a tractable therapeutic target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1858. doi:10.1158/1538-7445.AM2015-1858