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
(ERα+), and targeting ERα directly with ERα 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 ERα-dependent cancer cell death through
a mechanism distinct from clinically approved ERα drugs, via
hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple
ERα+ tumor models. While ErSO has promise as a
new drug, it has effects on ERα-negative (ERα−)
cells in certain contexts. Herein, we construct modified versions
of ErSO and identify variants with enhanced differential
activity between ERα+ and ERα– cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has
enhanced selectivity for ERα+ cancer cells, and is well tolerated
in rodents. ErSO-DFP and related compounds represent
an intriguing new class for the treatment of ERα+ cancers.