Brilanestrant (GDC-0810) is a selective estrogen receptor degrader (IC50: 0.7 nM).

ERα:0.7 nM

Brilanestrant是一种ERα结合剂（IC50: 6.1 nM），具有完全的转录拮抗作用而无激动作用（3× ERE, IC50: 2 nM），在ER-α降解（EC50: 0.7 nM）及MCF-7乳腺癌细胞活性（IC50; 2.5 nM）检测中展现出良好的效能和效果[1]。Brilanestrant诱导ERα形态与他莫昔芬及其他ER化合物吾不同，并在MCF7细胞中不表现出类似他莫昔芬的ER激动作用[2]。

Brilanestrant的药代动力学特性表明，其是一种跨物种的清除分子，具有良好的生物可用性（40%-60%）。在达玛新敏感的MCF-7异种移植模型中，Brilanestrant（3 mg/kg，p.o.）显著抑制肿瘤生长，而在最高剂量100 mg/kg/天时，所有动物的肿瘤退缩超过50%，且没有体重损失[1]。Brilanestrant表现出低清除率（11 mL/min/kg）和61%的口服生物可用性。Brilanestrant（1-100 mg/kg/天，p.o.）在MCF7异种移植模型中显示出剂量依赖性的疗效[2]。

MCF-7 cells are adjusted to a concentration of 40000 cells per mL in RPMI containing 10% FBS and 20 mM HEPES. Then 16 μL of the cell suspension (640 cells) is added to each well of a 384-well plate, and the cells are incubated overnight to allow the cells to adhere. The following day a 10-point, serial 1:5 dilution of each compound is added to the cells in 16 μL at a final concentration ranging from 10 to 0.000005 μM. After 5 days' compound exposure, 16 μL of CellTiter-GLo is added to the cells, and the relative luminescence units of each well are determined. CellTiter-GLo added to 32 μL of medium without cells is used to obtain a background value. The percent viability of each sample is determined as follows: RLU sample-RLU background/RLU untreated cells-RLU background ×100=%viability.

Time release pellets containing 0.72 mg 17-β estradiol are subcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMI containing 10% FBS at 5% CO2 37°C. Trypsinized cells are pelleted and resuspended in 50% RPMI（serum free）and 50% Matrigel at 1×107 cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on the right flank 2-3 days post pellet implantation. Tumor volume (length × width2/2) is monitored biweekly. When tumors reach an average volume of appr 200 mm3 animals are randomized and treatment is started. Animals are treated with vehicle or compound daily for 4 weeks. Tumor volume and body weight are monitored biweekly throughout the study.