The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice

Abstract

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women's health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer. The search for the 'ideal' SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained. In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.

Fig. (1)

Timeline of the major landmarks in estrogen action, anti-estrogens and SERMs for the treatment and prevention of breast cancer, and osteoporosis.

Fig. (2)

Molecular networks potentially influence the expression of SERM action in a target tissue. The shape of the ligands that bind to the estrogen receptors (ERs)α and β programmes the complex to become an estrogenic or anti-estrogenic signal. The context of the ER complex (ERC) can influence the expression of the response through the numbers of co-repressors (CoR) or coactivators (CoA). In simple terms, a site with few CoAs or high levels of CoRs might be a dominant anti-estrogenic site. However, the expression of estrogenic action is not simply the binding of the receptor complex to the promoter of the estrogen-responsive gene, but a dynamic process of CoA complex assembly and destruction [101]. A core CoA, for example, steroid receptor coactivator protein 3 (SRC3), and the ERC are influenced by phosphorylation cascades that phosphorylate target sites on both complexes. The core CoA then assembles an activated multiprotein complex containing specific co-co-activators (CoCo) that might include p300, each of which has a specific enzymatic activity to be activated later. The CoA complex (CoAc) binds to the ERC at the estrogen-responsive gene promoter to switch on transcription. The CoCo proteins then perform methylation (Me) or acetylation (Ac) to activate dissociation of the complex. Simultaneously, ubiquitiylation by the bound ubiquitin-conjugating enzyme (Ubc) targets ubiquitin ligase (UbL) destruction of protein members of the complex through the 26S proteasome. The ERs are also ubiquitylated and destroyed in the 26S proteasome. Therefore, a regimented cycle of assembly, activation and destruction occurs on the basis of the preprogrammed ER complex [101]. However, the co-activator, specifically SRC3, has ubiquitous action and can further modulate or amplify the ligand-activated trigger through many modulating genes [215] that can consolidate and increase the stimulatory response of the ERC in a tissue. Therefore, the target tissue is programmed to express a spectrum of responses between full estrogen action and anti-estrogen action on the basis of the shape of the ligand and the sophistication of the tissue-modulating network. NFκB, nuclear factor κB. This figure is published with permission from Nature Publishing group. Jordan, V.C. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nature Reviews Cancer, 2007 Jan; 7(1): 46-53.

Fig. (3)

Chemical structure of estradiol and selective estrogen receptor modulators (SERMs); raloxifene, tamoxifen, toremifene, ospemifene, lasofoxifene, arzoxifene and bazedoxifene.

Fig. (4)

Origins of current selective ER modulators for earlier nonsteroidal antiestrogens. Ospemifene is a known metabolite of the breast metabolite of the breast cancer drug toremifene. The metabolite of toremifene was found because an analogous metabolite Y was discovered for tamoxifen in the early 1980’s [119]. Lasofoxifene has its origins with failed antifertility agent discovered in the early 1960’s U-11, 100A [121]. The compound renamed nafoxidine was tested as a drug for the treatment of breast cancer but again failed because of serious side effects [123]. Bazedoxifene is an adaptation of an estrogenic metabolite from a failed breast cancer drug Zindoxifene [124]. Arzoxifene is the final compound in the lineage to find the optimal long acting SERM from the discovery that the hydroxylated metabolite of tamoxifen 4-hydroxytmaoxifen has a very high binding affinity for ER [35]. Raloxifene was a direct result of this discovery which became a successful SERM in clinical practice.

Fig. (5)

Progress toward an ideal SERM. The overall good or bad aspects of administering hormone replacement therapy to postmenopausal women compared with the observed site-specific actions of the selective estrogen receptor modulators tamoxifen and raloxifene. The known beneficial or negative actions of SERMs have opened the door for drug discovery to create the ideal SERM or targeted SERMs to either improve quality of life or prevent diseases associated with aging in women. This figure is published with permission from Elsevier. Jordan, V.C. Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell, 2004 Mar; 5(3): 207-213.