Drugs that inhibit estrogen receptor alpha (ERα) or which block the production of estrogens remain frontline interventions in the treatment and management of breast cancer at all stages. In this study, researchers found that molecular mechanism of action at estrogen receptor α of GW7604. GW7604 is a clinically relevant antiestrogen related to Tamoxifen. Especially, GW5638 is a prodrug that converts to its active metabolite, GW7604, similar to the way Tamoxifen converts to the metabolite 4-hydroxytamoxifen (4-OHT). GW7604 is an orally bioavailable selective estrogen receptor downregulator (SERD).

GW7604 is an antiestrogen at the TGFα gene. Moreover, GW7604 is particularly interesting for several reasons. Fisrtly, GW7604 has a unique structure as an antiestrogen. Secondly, GW7604 destroys estrogen receptor alpha in a manner similar to that of pure antiestrogens. Besides, GW7604 inhibits both estradiol (1 nM) and 4-OHT (10, 100 nM) induction of TGFα in a concentration related manner (1 nM-1 μM). Particularly, GW7604 and Raloxifene stimulates TGFα with the D351Y estrogen receptor. GW7604 has reduced estrogen-like actions at the TGFα gene and can block both E2 and 4-OHT induction of TGFα mRNA. As a result, GW7604 is therefore used in cell culture systems to study mechanisms of action at the ER in much the same way as 4-OHT is used in studies of Tamoxifen in vitro. Clearly the actions of GW5638 in vivo classify it as a selective estrogen receptor modulator.

Taken together, researchers conclude that GW7604 is a Raloxifene-like compound with anti-estrogen activity.

Bentrem D, et al. Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen. Endocrinology. 2001 Feb;142(2):838-46.