From empirical to mechanism-based discovery of clinically useful Selective Estrogen Receptor Modulators (SERMs)

Abstract

Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the Selective Estrogen Receptor Modulators (SERMs) tamoxifen and raloxifene, drugs whose estrogen receptor (ER) agonist/antagonist properties are influenced by the cell context in which they operate. These studies have revealed that notwithstanding differences in drug pharmacokinetics, the activity of an ER ligand is determined primarily by (a) the impact that a given ligand has on the receptor conformation and (b) the ability of structurally distinct ER-ligand complexes to interact with functionally distinct coregulators. Exploitation of the established relationships between ER structure and activity has led to the development of improved SERMs with more favorable therapeutic properties and of tissue-selective estrogen complexes, drugs in which a SERM and an ER agonist are combined to yield a blended activity that results in distinct clinical profiles. Remarkably, endogenous ligands that exhibit SERM activity have also been identified. One of these ligands, 27-hydroxycholesterol (27HC), has been shown to manifest ER-dependent pathological activities in the cardiovascular system, bone and mammary gland. Whereas the physiological activity of 27HC remains to be determined, its discovery highlights how cells have adopted mechanisms to allow the same receptor ligand complex to manifest different activities in different cells, and also how these processes can be exploited for new drug development.

Keywords: Estrogen receptor; SERM; Selective estrogen receptor modulator; TSEC; Tamoxifen.

Figure 1. Estrogen receptor (ER) pharmacology

Until relatively recently it was considered that the role of an ER-agonist was that of a “switch” which upon binding converted the receptor into an active state. Antagonists, on the other hand were believed to function by competitively inhibiting agonist binding thus freezing the receptor in an inactive state. However, it is now known that the overall conformation of ER is determined by the ligand to which it is bound, which in turn impacts the ability of the receptor to engage functionally different coregulators. Pure agonists enable the interaction of the receptor with coactivators (CoA), while antagonists allow the receptor to interact with only corepressors (CoR). Selective estrogen receptor modulators (SERMs) permit the bound ERs to interact with different subsets of coactivators and corepressors, determined by the overall receptor conformation associated with a given SERM, thereby permitting these drugs to elicit different activities in different tissues. Thus, the cellular response to an ER-agonist complex will be primarily determined by the relative expression level and activity of functionally distinct coregulators in different target tissues.

Figure 2. SERMs exert a spectrum of activities in estrogen target tissues

Like estradiol, all selective estrogen receptor modulators (SERMs) described to date increase and/or maintain bone mineral density (BMD), although SERMs do not elicit as robust of response as do full agonists. Fulvestrant is associated with decreased BMD. Similarly, the antagonist activities of different SERMs in the breast are not equivalent. Stimulation of uterine hypertrophy is the primary response that distinguishes SERMs, a liability of tamoxifen that has been reduced in second and third generation SERMs. It is the uterine response that most clearly determines the safety profile of a given SERM.

Figure 3

Comparison of the pharmacological activities of 17β-estradiol and the endogenous selective estrogen receptor modulator 27-hydroxycholesterol (27HC) in estrogen target tissues