Abstract 1619: Generation of a novel estrogen receptor degrader

Abstract

Abstract Fulvestrant is an effective therapy to treat post-menopausal women with estrogen receptor (ER)-positive metastatic breast cancer. The compound works as a selective estrogen receptor degrader (SERD). Structurally similar to estrogen, fulvestrant binds to the ligand binding domain (LBD) of the ER, altering the stability of the protein, leading to its accelerated proteasomal degradation. While effective, fulvestrant must be given intramuscularly, which has limited its clinical adoption. Based on the success of fulvestrant, multiple attempts have been made to generate orally available SERDs. These attempts have focused on compounds that, like fulvestrant, bind within the LBD of the ER. Overall, these intensive efforts have generated limited success. We reasoned that it may be possible to identify potential SERDs that bind to the ER in regions outside the LBD. Such an approach would be useful for tumors bearing wildtype ER, and likely for those bearing a mutant form of the ER, since most mutations cluster in the LBD. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bind outside of the LBD, and in particular to the N-terminal region of the ER. This strategy identified CL-ER-100, a small molecule that directly bound to the N-terminal region of the ER and functioned as a SERD. While CL-ER-100 rapidly induced ER proteasomal-dependent degradation, it had no effect on the protein levels of other, structurally related nuclear receptors. Based on its structure and size (~ MW 300 Da), CL-ER-100 is expected to have excellent bioavailability. Consistent with its binding outside of the LBD, addition of tamoxifen had no effect on the ability of CL-ER-100 to induce ER protein degradation. In cells, CL-ER-100 was able to markedly inhibit the growth of breast cancer cell lines such as MCF7 and T47D (IC50 of ~ 100 nM) while not inhibiting the growth of a wide array of normal and non-breast cancer tumor cell lines. Taken together, these results identify a novel strategy to develop small molecule SERDs that induce ER protein degradation by binding to previously untargeted regions of the estrogen receptor. Citation Format: Yuan Liu, Jason R. Kennerdell, Bo Lin, Mads B. Larsen, Irene Alfaras, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Generation of a novel estrogen receptor degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1619.