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

Ning, M.; Zhou, C.; Weng, J.; Zhang, S.; Chen, D.; Yang, C.; Wang, H.; Ren, J.; Zhou, L.; Jin, C.; Wang, M.-W.

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 ERα than ERβ were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ERα or ERβ and oestrogen-response element-driven luciferase. The estimated IC50 value was 0.52 nM for ERα and 2.94 nM for ERβ, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 μM. 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.British Journal of Pharmacology (2007) 150, 19–28. doi:10.1038/sj.bjp.0706960; published online 20 November 2006

SELECTIVE estrogen receptor modulators; RALOXIFENE; ESTROGEN; MAMMARY glands; UTERUS; BREAST cancer research; OSTEOPOROSIS

British Journal of Pharmacology, 2007, Vol 150, Issue 1, p19

0007-1188

Academic Journal

10.1038/sj.bjp.0706960