THU554 Unconventional Estrogen Receptor Antagonists Reveal Cryptic Therapeutic Anti-breast Cancer Transcriptional Pathways

Disclosure: G. Hancock: None. K. Young: None. G.L. Greene: None. S.W. Fanning: Advisory Board Member; Self; Olema Oncology. Grant Recipient; Self; Olema Oncology. Breast cancer is the most diagnosed cancer and 2nd leading cause of cancer-related death in women worldwide. The luminal subtype accounts for ∼70% of this heterogeneous disease. Standard of care for these estrogen receptor alpha (ERα) positive diseases includes 5 years of adjuvant endocrine therapy in the form of aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs). Despite therapeutic advances, approximately half of ERα+ patients develop resistance to these endocrine therapies. In this study, x-ray crystallography of SERMs and SERDs link structural characteristics to transcriptional activity in order to understand mechanisms of antiestrogen efficacy in ER+ drug resistant breast cancers. A new class of antiestrogen based on a tetrahydro-6-isoquinoline (T6I) scaffold was developed to antagonize ERα by adopting unique binding poses to inhibit coactivator binding to the ligand binding domain (LBD). Optimization of structure-activity relationships produced unique antiestrogenic activities and a lead compound that induces transcriptional programs similar to fulvestrant despite its SERM-like accumulation of ERα in the breast cancer cell. Like fulvestrant, this T6I uniquely induces the expression of small ubiquitin-like modifier-1 (SUMO1), in opposition to 17β-estradiol. Together, this study uses structurally unique antiestrogens to further the understanding of key functional components of estrogen therapies. Presentation: Thursday, June 15, 2023