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


METHODS
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.


RESULTS
Five analogues, belonging to two different structural series and display higher binding affinities for ERalpha than ERbeta were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ERalpha or ERbeta and oestrogen-response element-driven luciferase. The estimated IC(50) value was 0.52 nM for ERalpha and 2.94 nM for ERbeta, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 microM. 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
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.
Ning
M
M
Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Zhangjiang High-tech Park, Pudong New District, Shanghai, China.
Zhou
C
C
Weng
J
J
Zhang
S
S
Chen
D
D
Yang
C
C
Wang
H
H
Ren
J
J
Zhou
L
L
Jin
C
C
Wang
M-W
MW
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014158:Transcription, Genetic; D014599:Uterus / Q000187:drug effects
D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C518540:Y134 compound; D020849:Raloxifene Hydrochloride