Biological activities of a novel selective oestrogen receptor modulator derived from raloxifene (Y134)

Abstract

Background and purpose: Selective oestrogen receptor (ER) modulators (SERMs) are of great value in the treatment of breast cancer and osteoporosis. The aim of this study was to characterize pharmacologically a new class of SERMs synthesized based on the core structure of raloxifene. Experimental approach: Competitive receptor binding and luciferase-based reporter methods were used to study the bioactivities of raloxifene analogues, followed by efficacy determination in breast cancer cell proliferation assay. ER antagonist effects were investigated in female rats by measuring uterine and mammary gland growth, using wet weight, BrdU incorporation and terminal end bud (TEB) as indicators. Key results: Five analogues, belonging to two different structural series and display higher binding affinities for ERa than ERb were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ERa or ERb and oestrogen-response element-driven luciferase. The estimated IC 50 value was 0.52 nM for ERa and 2.94 nM for ERb, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 mM. Y134 suppressed oestrogen-stimulated proliferation of ER-positive human breast cancer MCF-7 and T47D cells. At an identical dose, administered to ovariectomized rats, Y134 was more effective than raloxifene at arresting oestrogen-induced outgrowth of TEB and mammary gland DNA synthesis, but their inhibitory effects on the uterus were comparable. Conclusions and Implications: Y134 is a potent ER antagonist with better mammary gland selectivity than raloxifene and shows potential for development as a new SERM for therapeutic use.

Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine

“…17-β-estradiol and progesterone (in olive oil) were purchased from Sigma (St. Louis, MO, USA). Raloxifene and Y134 (a derivative of raloxifen with an IC 50 at 0.52 and 2.94 nM for α and β estrogen receptor, respectively; Ning et al 2007) were synthesized by a chemical synthesis program in Shanghai Institute of Materia Medica, dissolved initially in DMSO and then diluted to desired concentrations with saline.…”

Estrogen Receptor α Antagonists Mediate Changes in CCL20 and CXCL1 Secretions in the Murine Female Reproductive Tract

“…ICI 182,780 (Faslodex) is an ER antagonist with a high affinity to both estrogen receptor subtypes 16, 17 . Y134 is highly selective for ERα over ERβ, and has shown to act as an antagonist in reproductive tissue 18, 19 . PHTPP specifically interacts with ERβ, and has shown to act as a full antagonist in human endometrial cancer cells 20 .…”

Recent Advances in Selective Estrogen Receptor Modulators for Breast Cancer

“…Y134 (Fig. 5), a raloxifene analog, was designed and synthesized [66]. It appeared to be more selective for ER (120-fold) and suppressed estrogen-stimulated proliferation of ER-positive breast cancer MCF-1 and T47D cells.…”