Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels

We compared the antitumor efficacy and estrogen receptor (ER) degradation of CH4893237, a new orally active selective ER downregulator, with fulvestrant and tamoxifen in human breast cancer xenografts with low levels of serum estrogen (E 2 ) (50.6, 22.9 and 90%) and tamoxifen (30 and 100 mg/kg/day p.o.) showed moderate tamoxifen resistance. The antitumor activity of CH4893237 (300 mg/kg) was the same as that of fulvestrant (3 mg/body) but the rate of ER degradation induced by CH4893237 (300 mg/kg) was significantly stronger than that of fulvestrant (3 mg/body) (94.3 vs. 85.5%, P 70%) whereas tamoxifen (1, 10 and 100 mg/kg) showed strong tamoxifen resistance. In Br-10 xenografts with ovariectomized-level E 2 (<16.7 pg/ml), tamoxifen (30 mg/kg) increased the tumor volume but CH4893237 (30 mg/kg) showed no agonistic activity. In the ERa and ERB proteolysis assays, the band pattern for CH4893237 was different from fulvestrant. Thus, CH48793237 showed potent antitumor efficacies without agonistic activity and superior ER degradation in human breast cancer xenografts with low serum E 2 . Furthermore, the proteolysis studies suggest that CH4893237 induces conformational changes of ER different from those induced by fulvestrant. Therefore, CH4893237 alone or in combination with an aromatase inhibitor may be an efficient treatment for postmenopausal breast cancer patients.