Structure–Activity Relationship Study of Tris-Benzamides as Estrogen Receptor Coregulator Binding Modulators

Estrogen receptor coregulator binding modulators (ERXs) are a novel class of molecules targeting the interaction between estrogen receptor α (ERα) and its coregulator proteins, which has proven to be an attractive strategy for overcoming endocrine resistance in breast cancer. We previously reported ERX-11, an orally bioavailable tris-benzamide, that demonstrated promising antitumor activity against ERα-positive breast cancer cells. To comprehend the significance of the substituents in ERX-11, we carried out structure–activity relationship studies. In addition, we introduced additional alkyl substituents at either the N- or C-terminus to improve binding affinity and biological activity. Further optimization guided by conformational restriction led to the identification of a trans-4-phenylcyclcohexyl group at the C-terminus (18h), resulting in a greater than 10-fold increase in binding affinity and cell growth inhibition potency compared to ERX-11. Tris-benzamide 18h disrupted the ERα-coregulator interaction and inhibited the ERα-mediated transcriptional activity. It demonstrated strong antiproliferative activity on ERα-positive breast cancer cells both in vitro and in vivo, offering a promising potential as a therapeutic candidate for treating ERα-positive breast cancer.