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Tumor Biology

SAT-289 - Development of Thienopyrimidine-Based Selective Estrogen Receptor Degraders for Breast Cancer

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Sophie Biehl, BA: No financial relationships to disclose
David Robert Zak, B.S.: No financial relationships to disclose
Emma Fink, BS: No financial relationships to disclose
Govinda Hancock, MS: No financial relationships to disclose
Seventy percent of breast cancers (BC) express estrogen receptor alpha (ERα, ESR1 gene), a nuclear hormone receptor that drives tumorigenesis, survival, and metastasis. Endocrine therapies (ETs), including aromatase inhibitors, selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs), disrupt ERα signaling to treat disease. Aromatase inhibitors lower the production of estrogen and have demonstrated significant benefits to BC patients; however, these treatments also can promote the expansion of cancer cells harboring ESR1 mutants. The Y537S ESR1 mutation, one of the most common ESR1 mutants in BC, promotes aggressive disease and therapeutic resistance, making this mutation a critical target for developing new endocrine therapies. SERMs and SERDs elicit anticancer activity by binding to the ERα ligand binding domain (LBD) and inducing alternative structural conformations, promoting the recruitment of ligand-specific transcriptional coregulators to reprogram the transcriptome. Next generation SERMs and SERDs demonstrate increased efficacy against ESR1 mutant BC, but the benefits are often non-durable. The development of noncanonical SERM/SERD chemical scaffolds presents an opportunity to create novel BC therapies through engaging ERα with a unique chemical space. The recently approved elacestrant (RAD1901) has been shown to adopt an unconventional ligand binding pose, but the structure-activity relationship of this pose has not yet been fully elucidated due to the lack of similar ligands. Our previous work showed via high-resolution x-ray co-crystal structures that thienopyrimidine-based ERα binding scaffolds bind ERα in a similar pose to RAD1901. In this study, we synthesized a panel of novel thienopyridine-based compounds to investigate the structure-activity relationships that give rise to therapeutic efficacy within this distinct chemical core. Our data show that a subset of thienopyrimidines inhibited cell proliferation and viability in WT and Y537S ESR1 BC cells, acted as complete antiestrogens in uterine cancer cells, and induced SERD-like ERα proteasomal degradation. These compounds also effectively inhibited the expression of canonical estrogen-sensitive ERα target genes in a cell-line and timepoint specific manner and disrupted ERα oncogenic coactivator recruitment in WT BC cells. X-ray co-crystal structures combined with atomistic molecular dynamics simulations show that these compounds uniquely affect ERα structural dynamics to elicit SERD-like activities. This study presents a new chemical scaffold that expands the chemical space that can be explored to develop novel ERα-targeted BC therapies.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*