The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood–brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing ESR1 mutations. A novel 3-oxyazetidine side chain was designed, leading to 37d, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.

Background Greater circulating levels of the steroid hormone 17β‐estradiol (E2) are associated with higher levels of binge drinking in women. In female mice, estrogen receptors in the ventral tegmental area, a dopaminergic region of the brain involved in the motivation to consume ethanol, regulate binge‐like ethanol intake. We recently developed a brain‐penetrant selective estrogen receptor degrader (SERD), YL3‐122, that could be used to test the behavioral role of brain estrogen receptors. We hypothesized that treating female mice with this compound would reduce binge‐like ethanol drinking. Methods Female C57BL/6J mice were treated systemically with YL3‐122 and a related SERD with low brain penetrance, XR5‐27, and tested for binge‐like ethanol consumption in the drinking in the dark (DID) test. Mice were also tested for sucrose and water consumption and blood ethanol clearance after treatment with the SERDs. Finally, the effect of ethanol exposure on Esr1 gene expression was measured in the ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral hippocampus (vHPC) of male and female mice by quantitative real‐time PCR after 4 DID sessions. Results YL3‐122 reduced ethanol consumption when mice were in diestrus but not estrus. YL3‐122 also decreased sucrose consumption but did not alter water intake or blood ethanol clearance. XR5‐27 did not affect any of these measures. Binge‐like ethanol drinking resulted in increased Esr1 transcript in the VTA of both sexes, male vHPC, and female PFC. Conclusions These results indicate that SERD treatment can decrease binge‐like ethanol drinking in female mice. Thus, it could be a novel strategy to reduce binge drinking in women, with the caveat that effectiveness may depend on menstrual cycle phase. In addition, Esr1 transcript is increased by binge ethanol exposure in both sexes but in a brain region‐specific manner.

1 out of every 8 U.S. women will develop invasive breast cancer during her lifetime, making it the second most common form of cancer affecting women. Breast cancer is also a leading cause of cancer related deaths for women in the U.S., second only to lung cancer. Activation of estrogen receptor alpha (ERα) is the primary proliferative mechanism of breast cancer cells, making it a logical target for therapy. ER ligands with antiestrogenic activity, such as the selective estrogen receptor modulator (SERM), tamoxifen, and selective estrogen receptor degrader (SERD), fulvestrant, have proven clinically successful as treatments for breast cancer; however, resistance in up to 50% of patients provides a therapeutic challenge. Once resistant, breast cancer cells become endocrine-independent, because of this, there is an urgent need for both novel therapy and improved models of resistant breast cancer. Our lab has created a panel of various endocrine-independent cell lines to mimic SERM and SERD resistance. Along with traditional 2D cell culturing, 3D spheroids have also been utilized to gain a better understanding of resistance. Importantly, the response to therapeutic agents, of cell lines in 2D versus 3D cultures is not identical. We observe that 3D cultures better replicate observations in mouse xenograft models, demonstrating that elements of the spheroid microenvironment, such as cell-cell interactions and the presence of extracellular matrix (EM), mimic aspects of the tumor microenvironment in vivo. Cells cultured as spheroids are therefore a suitable in vitro model for drug discovery, predictive of response in preclinical animal models, in contrast to 2D monolayer cell cultures. Citation Format: Carlo I. Rosales, Jiong Zhao, Lauren M. Gutgesell, Rui Xiong, Debra A. Tonetti, Gregory R. Thatcher. Three-dimensional treatment-resistant breast cancer spheroids as a predictive model of in vivo response to endocrine therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3738.

The estrogen receptor (ER) has historically played and continues to play a prominent role in drug discovery as a target for medicinal chemists. The first targeted cancer therapy was directed at ERα and the first clinical drug that is a proteolysis targeting small molecule is also an ER ligand used to treat metastatic breast cancer. The last decade has been described as a renaissance in the medicinal chemistry of endocrine therapy, therefore, this article focuses on design of small molecule ERα ligands for treatment of hormone‐dependent breast cancer. As our understanding of the role of ER in resistance to endocrine therapy increases, further opportunities will be presented for medicinal chemists to design therapeutic agents for metastatic disease. Beyond breast cancer, ER, whether nuclear or extranuclear remains largely unexploited as a target for small molecule drug design, which is partly explained by the complexity of the underlying biology and partly by the cooling influence of the initial Women's Health Initiative outcomes on estrogen replacement therapy. Old and new concepts of ligand binding and signal transduction by ER are presented to stimulate the interests of medicinal chemists; accompanied by a catalogue of newer small molecule ligands reported in the literature and their interactions with ER.