ER Inhibitors

ER inhibitors are a diverse group of compounds that interact with the estrogen receptor (ER) in various ways to inhibit its activity. The primary function of the ER is to bind estrogen, which then causes the receptor to undergo a conformational change, allowing it to regulate the expression of genes involved in numerous physiological processes. Inhibitors of the ER can prevent the normal action of estrogen either by directly blocking the receptor or by reducing the levels of the hormone available for binding.

SERMs, such as tamoxifen, raloxifene, clomiphene, toremifene, and bazedoxifene, are compounds that bind to the ER and alter its shape, which can prevent the receptor from interacting with the DNA in the correct manner, thus inhibiting gene transcription that would normally be activated by estrogen. Each SERM has a distinct set of tissue-specific effects, acting as either an agonist or antagonist depending on the target tissue. For instance, tamoxifen can block estrogen's effects in breast tissue but act as an estrogen agonist in bone and uterine tissues. SERDs like fulvestrant bind to the ER and promote its degradation. Unlike SERMs, SERDs do not have agonistic effects in any tissues and lead to a decrease in the total number of estrogen receptors available within a cell. Aromatase inhibitors, including letrozole, anastrozole, exemestane, and formestane, work by inhibiting the enzyme aromatase, which is responsible for converting androgens into estrogens. With reduced estrogen synthesis, the activation of ER by estrogen is decreased. Additionally, compounds like goserelin and leuprolide, which are GnRH agonists, initially stimulate the release of gonadotropins but eventually lead to decreased gonadotropin levels due to receptor downregulation. This, in turn, leads to reduced estrogen production from the ovaries, resulting in lowered ER activation.