Thiochroman derivative CH4986399, a new nonsteroidal estrogen receptor down-regulator, is effective in breast cancer models.
BACKGROUND
Tamoxifen, a selective estrogen receptor modulator, and fulvestrant, a selective estrogen receptor down-regulator (SERD), are now available for estrogen receptor-positive breast cancer patients. However, these patients acquire drug-resistance during the treatments. We identified a new orally active nonsteroidal SERD, CH4986399, which is structurally unrelated to fulvestrant and tamoxifen.


METHODS
We examined the oral antitumor activity and down-regulation of ER by CH4986399 in human breast cancer Br-10 and ZR-75-1 xenografts.


RESULTS
In the Br-10 xenografts, CH4986399 (100 mg/kg p.o.) as well as fulvestrant (3 mg/body s.c.) strongly reduced tumor weight. In the ZR-75-1 xenografts, CH4986399 (100 mg/kg p.o.) strongly reduced tumor weight and ER content without agonistic activity. In contrast, tamoxifen (100 mg/kg p.o.) showed only moderate antitumor activity and no ER down-regulation.


CONCLUSIONS
With a chemical structure different from both fulvestrant and tamoxifen, CH4986399, may help overcome drug resistance from the endocrine treatment sequence for breast cancer patients.
Yoneya
Takaaki
T
Kamakura Research Laboratories, 200 Kajiwara Kamakura, Kanagawa 247-8530, Japan. yoneyatka@chugai-pharm.co.jp
Taniguchi
Kenji
K
Nakamura
Ryo
R
Tsunenari
Toshiaki
T
Ohizumi
Iwao
I
Kanbe
Yoshitake
Y
Morikawa
Kazumi
K
Kaiho
Shin-Ichi
S
Yamada-Okabe
Hisafumi
H
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000096:biosynthesis; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D019086:Bridged Bicyclo Compounds, Heterocyclic; C549427:CH 4986399; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators