Abstract
Many synthetic selective estrogen receptor modulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that increased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihydrobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible explanation of the counterintuitive results of TAM therapy.
Highlights
It has been widely asserted that the incidence of breast cancer is 1 in 8 women over the course of lifetime in the United States
A generally accepted mechanism is that TAM, and most selective estrogen receptor modulators (SERMs), stabilize the estrogen receptor α ligand binding domain (ERα LBD) in the canonical inactive conformation, which differs from the estradiol induced active conformation
The crystal structures demonstrate that SERMs stabilize a canonical inactive conformation of the ERα LBD
Summary
It has been widely asserted that the incidence of breast cancer is 1 in 8 women over the course of lifetime in the United States. 70% of all breast cancers are hormone receptor positive and the patients will likely be treated by tamoxifen (TAM), the most commonly used selective estrogen receptor modulator (SERM), which exerts tissue-selective effects [1]. TAM works as an estrogen antagonist in breast cells, significantly reducing the risk of breast cancer recurrence [2,3]. It works as an estrogen agonist in bone, in the cardiovascular system and in uterine tissue [4], with the undesirable utertropic side-effect of increased incidence of endometrial cancer [5]. A generally accepted mechanism is that TAM, and most SERMs, stabilize the estrogen receptor α ligand binding domain (ERα LBD) in the canonical inactive conformation, which differs from the estradiol induced active conformation. TAM and its metabolites competitively bind to the tumor ER, thereby blocking the binding of estrogen and inhibiting estrogen-induced tumor cell growth
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