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 (E2) (50.6, 22.9 and <16.7 pg/ml), equivalent to the ranges in postmenopausal or
aromatase inhibitor-treated
breast cancer patients. In addition, using proteolysis assays, we tested the conformational changes induced in
ERalpha and
ERbeta by
CH4893237,
fulvestrant, and 4-OH
tamoxifen (4OHT). In ZR-75-1 xenografts with 50.6 pg/ml E2,
CH4893237 (100 and 300 mg/kg/day p.o.) as well as
fulvestrant (1 and 3 mg/body/week s.c.) showed complete growth inhibition (>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<0.01). In Br-10 xenografts with 22.9 pg/ml E2,
CH4893237 (30 mg/kg) and
fulvestrant (1 mg/body) showed potent growth inhibition (>70%) whereas
tamoxifen (1, 10 and 100 mg/kg) showed strong
tamoxifen resistance. In Br-10 xenografts with ovariectomized-level E2 (<16.7 pg/ml),
tamoxifen (30 mg/kg) increased the
tumor volume but
CH4893237 (30 mg/kg) showed no agonistic activity. In the
ERalpha and
ERbeta 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 E2. 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.