Brilanestrant (GDC-0810)

製品コードS7855 バッチS785501

印刷

化学情報

Chemical Structure Synonyms ARN-810 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C26H20ClFN2O2
分子量 446.90 CAS No. 1365888-06-7
Solubility (25°C)* 体外 DMSO 89 mg/mL (199.14 mM)
Ethanol 89 mg/mL (199.14 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Brilanestrant (GDC-0810, ARN-810) は強力なER-α結合剤（ER-α, IC50 = 6.1 nM; ER-β, IC50 = 8.8 nM）であり、アゴニスト活性を持たない完全な転写アンタゴニストです。Brilanestrantは、ER-α分解（EC50 = 0.7 nM）およびMCF-7乳がん細胞生存率（IC50 = 2.5 nM）アッセイにおいて、他の核内ホルモン受容体に対する良好な選択性と共に、優れた効力と有効性を示します。
in vitro In cell-free radio-ligand competitive binding assays, Brilanestrant (GDC-0810) binds both ERα and ERβ with low nanomolar affinity. This compound has little to no inhibition against CYP1A2, CYP2D6, or CYP3A4 (IC50 > 20 μM), modest inhibitory effect on CYP2C9 and CYP2C19 (IC50 = 2.2 and 3.3 μM respectively), and potent inhibition of CYP2C8 (IC50 of <0.1 μM). Selectivity of it over other nuclear hormone receptors is also found to be good. In transcriptional reporter assays for the mineralocorticoid (MR), progesterone-A (PR-A), progesterone (PR-B), and glucocorticoid (GR) receptors, it has minimal activity (IC50 > 1 μM). While in binding assays, it displays little activity toward the androgen receptor (AR; IC50 > 4 μM) and GR (IC50 = 0.99 μM). GDC-0810-mediated ERα depletion is dependent on the 26S proteasome. It antagonizes ERα ligand binding domain mutants in vitro and in vivo. In cell-free E2 competitive binding assays that was used to determine the binding of this compound to ER.WT, ER.Y537S and ER.D538G ligand binding domains, it retains its ability to potently displace E2 from the ligand binding domain, albeit with a slightly increased IC50 (WT: 2.6 nM vs. ER.Y537S: 5.5 nM and ER.D538G: 5.4 nM). It can compete the PGC1α co-activator peptide off the mutated ligand binding domain, implying that it is capable of driving an 'active' to 'inactive' conformational shift of mutant ER, though with a ~five-seven fold reduction in biochemical potency compared to wild-type ER.
in vivo Brilanestrant (GDC-0810) exhibits a pharmacokinetic profile characterized by low clearance across species and good bioavailability (40–60%). As would be expected for a lipophilic carboxylic acid, the compound is highly bound to plasma proteins (>99.5% across species) and has a low to moderate volume of distribution (Vss = 0.2–2.0 L/kg across species). It demonstrates good bioavailability across species and displays robust activity in tamoxifen-sensitive and tamoxifen-resistant xenograft models of breast cancer. This compound also exhibits mild estrogenic activity in uterine models in vitro and in vivo.

プロトコル(参考用のみ)

細胞アッセイ 細胞株 MCF-7 cells
濃度 --
反応時間 4 h
実験の流れ

MCF-7 cells are trypsinized and washed twice in phenol red free RPMI containing 5% charcoal dextran stripped FBS with 20 mM HEPES and NEAA and adjusted to a concentration of 200000 cells per mL with the same medium. Next, 16 μL of the cell suspension (3200 cells) is added to each well of a poly-D-lysine coated 384-well plate, and the cells are incubated at 37℃ over 4 days to allow the cells to adhere and grow. On day 4, a 10-point, serial 1:5 dilution of Brilanestrant (GDC-0810) is added to the cells in 16 μL at a final concentration ranging from 10−5 M to 5.12 × 10−12 M or 10−6 M to 5.12 × 10−13 M for fulvestrant. At 4 h post compound addition, the cells are fixed by adding 16 μL of 30% formalin to the 32 μL of cells and this compound (10% formalin final concentration) for 20 min. Cells are then washed twice with PBS Tween 0.1% and then permeabilized in PBS 0.1% Triton (50 μL/well) for additional 15 min. The PBS 0.1% triton is decanted, and the cells are washed: LI-COR blocking buffer (50 μL/well) was added, the plate is spun at 3000 rpm, and then the blocking buffer is decanted. Additional LI-COR blocking buffer (50 μL/well) is added, and the cells are incubated overnight at 4℃. The blocking buffer is decanted, and the cells are incubated overnight at 4℃ with SP1 anti-ER rabbit monoclonal antibody diluted 1:1000 in LI-COR blocking buffer/0.1% Tween-20. Wells, which are treated with blocking buffer with Tween but no antibody, are used as a background control. Wells are washed twice with PBS Tween 0.1% to remove free SP1 antibodies, and the cells are incubated at room temp for 60−90 min in LI-COR goat antirabbit IRDyeTM 800CW (1:1000) and DRAQ5 DNA dye diluted in LI-COR blocking buffer containing 0.1% Tween-20 and 0.01% SDS. Cells are then washed with 0.1%Tween-20/PBS three times. Plates are scanned on a LI-COR Odyssey infrared imaging system.
動物実験 動物モデル a tamoxifen-sensitive MCF-7 xenograft model
投薬量 30 and 100 mg/kg
投与方法 p.o.

参考

  • https://pubmed.ncbi.nlm.nih.gov/25879485/
  • https://pubmed.ncbi.nlm.nih.gov/27410477/

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer. [ Breast Cancer Res Treat, 2020, 10.1007/s10549-020-05575-9] PubMed: 32130619
Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies. [ Nat Genet, 2019, 51(2):207-216] PubMed: 30531871

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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