GDC-0810 is a potent ER-α binder (IC50=6.1 nM), a full transcriptional antagonist with no agonism (3× ERE, IC50=2 nM), and displays good potency and efficacy in ER-α degradation (EC50=0.7 nM) and MCF-7 breast cancer cell viability (IC50=2.5 nM) assays.
GDC-0810 (3 mg/kg, p.o.) shows substantial tumor-growth inhibition in a tamoxifen-sensitive MCF-7 xenograft model, while at the highest dose of 100 mg/kg/day, all animals show tumor regression of more than 50% without weight loss. GDC-0810 exhibits low clearance (11 mL/min/kg) and 61% oral bioavailability. GDC-0810 (1-100 mg/kg/day, p.o.) displays dose dependent efficacy in the MCF7 xenograft model.
|Cell lines||MCF-7 cells|
|Preparation method||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).|
|Incubation time||5 days|
|Animal models||tamoxifen-sensitive MCF-7 xenograft model|
|Formulation||PEG400/PVP/TW80/0.5% CMC in water, 9:0.5:0.5:90|
|Dosages||30 and 100 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 60 mg/mL|
The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.
Joseph JD, et al. Elife. 2016 Jul 13;5. pii: e15828. PMID: 27410477.
Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
Lai A, et al. J Med Chem. 2015 Jun 25;58(12):4888-904. PMID: 25879485.
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