title: Identification of a novel, orally bioavailable estrogen receptor downregulator.
abstract: Tamoxifen has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer, but its partial agonist activity is considered to limit the efficacy, and cause tumor flare and endometrial cancer. Fulvestrant, on the other hand, binds and degrades ER, thereby acting as a pure anti-estrogen without partial agonist activity. However, due to its low oral bioavailability, fulvestrant has to be intramuscularly administered to patients, which limits the convenience of the drug, and causes pain and inflammation at the site of injection. In search of a patient- friendly pure anti-estrogen, we screened and identified an ER antagonist, CH4893237, which bound to ER with an IC50 value of 1.4 muM and, by oral administration, inhibited estrogen-stimulated uterine growth in ovariectomized mice. CH4893237 reduced the amount of ER at the protein level and impaired the nuclear accumulation of ER, indicating an orally active pure anti-estrogen. Furthermore, CH4893237 inhibited the estrogen-stimulated proliferation of MCF-7, ZR-75-1 and BT-474 cells, and caused a marked growth inhibition of the MCF-7 xenograft in vivo. Thus, CH4893237 will provide an additional option for second-line hormone treatment of breast cancer.
authors: Pharmaceutical Research Department III, Chugai Pharmaceutical, Kanagawa and Shizuoka, Japan.
authors: Takaaki
authors: T
authors: Yoneya
authors: Kenji
authors: K
authors: Taniguchi
authors: Toshiaki
authors: T
authors: Tsunenari
authors: Hidemi
authors: H
authors: Saito
authors: Yoshitake
authors: Y
authors: Kanbe
authors: Kazumi
authors: K
authors: Morikawa
authors: Hisafumi
authors: H
authors: Yamada-Okabe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C508478:CH 4893237; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D004958:Estradiol