Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells

Estrogen receptor alpha (ER alpha) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ER alpha conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ER alpha genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ER alpha structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ER alpha ligand binding pocket. They show moderately reduced antagonistic potencies on ER alpha genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ER alpha in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ER alpha accumulation in breast cancer cells.

Automated summary

This study identified chemically unconventional antagonists of estrogen receptor alpha (ERα) that have moderate effects on the transcriptional activities of breast cancer cells, exhibit anti-proliferative properties, and engage transcriptional pathways similar to selective estrogen receptor degraders.