title: Thiochroman derivative CH4986399, a new nonsteroidal estrogen receptor down-regulator, is effective in breast cancer models.
abstract: 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.
authors.affiliation: Kamakura Research Laboratories, 200 Kajiwara Kamakura, Kanagawa 247-8530, Japan. yoneyatka@chugai-pharm.co.jp
authors.forename: Takaaki
authors.initials: T
authors.lastname: Yoneya
authors.forename: Kenji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakamura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tsunenari
authors.forename: Iwao
authors.initials: I
authors.lastname: Ohizumi
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Kanbe
authors.forename: Kazumi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kaiho
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
mesh_terms: 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
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C549427:CH 4986399; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators