2', 3', 4'-Trihydroxychalcone is an Estrogen Receptor Ligand which Modulates the Activity of 17-β Estradiol

Menopausal hormone therapy (MHT) reduces the risk of osteoporosis, fractures, obesity and diabetes, but long-term MHT increases risk of other diseases. Safe long-term MHT that exploits its benefits and abrogates its adverse effects requires a new approach. Here we demonstrate that a trihydroxychalcone (CC7) acts as an estrogen receptor alpha ligand that may improve the safety profile of MHT. CC7 reprograms the actions of estradiol (E2) to regulate unique genes in bone-derived U2OS cells, with 824/1358 genes not regulated by E2. The proliferative action of E2 on human MCF-7 breast cancer cells and mouse uterus is blocked when combined with CC7. Thermostability and molecular dynamics simulation studies suggest that CC7 binds concurrently with E2 in the estrogen receptor alpha ligand binding pocket to produce a unique coliganded conformation to modulate estrogen receptor alpha. Compounds such as CC7 that act as coligands represent a new class of estrogen receptor alpha reprograming drugs that potentially can be combined with existing estrogens to produce a safer MHT regimen for long-term therapy.