Estrogen Receptor Modulators and Down Regulators

Abstract

Endocrine treatments have been used in breast cancer since 1896, when Beatson reported on the results of oophorectomy for advanced breast cancer. In the second half of the last century, different endocrine-based compounds were developed and, in this review, the role of the selective estrogen receptor modulators (SERMs) and selective estrogen receptor down regulators (SERDs) in the postmenopausal setting are discussed. Tamoxifen is the most investigated and most widely used representative of these agents, and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting, and for the prevention of the disease. Its role has been challenged in recent years by the introduction of third-generation aromatase inhibitors that have proven higher activities than tamoxifen with different toxicity patterns. Several other SERMs have been investigated, but none have been clearly superior to tamoxifen. SERDs act as pure estrogen antagonists and should compare favourably to tamoxifen. For the time being, they have been used in the treatment of advanced breast cancers and their role in other settings still needs investigation. The increased use of aromatase inhibitors as first-line endocrine therapy has resulted in new discussions regarding the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies in hormone-sensitive breast cancer remains a very important research issue.

Synthesis of targeted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines as potential lead molecules with promising anti-breast cancer activity

“…In spite of these beneficial effects, estradiol stimulation also influences the pathological processes of hormone-dependent cancers of breast, endometrial, prostrate, ovary and many other type of malignant tumors [5,6]. The important finding of the hormone responsiveness of ER+ve breast cancers, triggered the development of molecules which can compete with estradiol at its receptor and counterbalance its proliferative action [7]. The discovery of non-steroidal antiestrogen, tamoxifen as the therapy of choice for patients with ER+ve breast cancer [8] revolutionized the approach to regulate the endocrine system by disrupting the signalling cascade.…”

Development of Cell-Penetrating R7 Fragment-Conjugated Helical Peptides as Inhibitors of Estrogen Receptor-Mediated Transcription

“…Although the inhibitory activity of the R7-conjugated peptide 5 against ER−coactivator interactions was slightly decreased compared with that of the R7-unconjugated peptide 2 (IC 50 : 13 nM), 5 still exhibited potent activity. The dominant conformations of the peptides were analyzed based on H-His-Lys-Ile-Leu-His-Arg-Leu-Leu-Gln-NH 2 PERM-1-R7 (4) H-Lys-cyclo(D-Cys-Ile-Leu-Cys)-Arg-Leu-Leu-Gln-(Gly) 3 -(Arg) 7 -NH 2 PERM-3-R7 (5) H-Arg-cyclo(D-Cys-Ile-Leu-Cys)-Arg-Npg-Leu-Gln-(Gly) 3 -(Arg) 7 -NH 2 SRC-1-R7 (6) H-His-Lys-Ile-Leu-His-Arg-Leu-Leu-Gln-(Gly) 3 -(Arg) 7 -NH 2 YR7 (7) H-Tyr-(Arg) 7 Information about the synthesis and purification of the peptides and the protocols of the in vitro assays. This material is available free of charge via the Internet at http://pubs.acs.org.…”

Discovery of coumarin–monastrol hybrid as potential antibreast tumor-specific agent

“…Since estrogens are well known to play crucial roles in breast cancer development, much effort has been devoted to block estrogen formation [2]. The most widely used therapy for antagonizing estrogen receptor (ER) function is the antiestrogen tamoxifen (TAM), which binds to the ER and blocks downstream signaling [3]. However, current breast cancer therapies with TAM achieve meaningful clinical results in only 40% of patients because drug resistance usually develops within couple of years of treatment.…”