Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer

Approximately 75% of breast cancers are estrogen receptor alpha-positive (ER alpha+), and targeting ER alpha directly with ER alpha antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ER alpha-dependent cancer cell death through a mechanism distinct from clinically approved ER alpha drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ER alpha+ tumor models. While ErSO has promise as a new drug, it has effects on ER alpha-negative (ER alpha-) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ER alpha+ and ER alpha- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ER alpha+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ER alpha+ cancers.