biostudies-literatureLee TKNational Cancer InstituteNCI NIH HHSWelch Foundation2023-2043https://www.ebi.ac.uk/biostudies/studies/S-EPMC11249634biostudies-literatureUnknown7(7)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 <i>trans</i>-4-pACS pharmacology & translational scienceStructure-Activity Relationship Study of Tris-Benzamides as Estrogen Receptor Coregulator Binding Modulators.PMC112496341R01CA223828R01 CA223828AT-1595R01 CA2627571R01CA262757Chen CYLee TKVadlamudi RKAhn JMKassees KViswanadhapalli SParra KfalseStructure-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 <i>trans</i>-4-p2024-01-01T00:00:00Z2024 Jul2026-06-01T13:55:07.513Z2026-04-08T13:04:44.01ZS-EPMC112496343902235010.1021/acsptsci.4c00125