GDC-0084

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer ³. GDC-0084 is a brain penetrant inhibitor of PI3K and mTOR, with Kiapp values of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively ⁴. GDC-0084 maintains inhibition of each of the Class I PI3K isoforms but with more potent inhibition of mTOR. GDC-0084 is also tested in five different GBM (glioblastoma multiforme) cell lines and is found to have antiproliferative EC50s ranging from 0.3 to 1.1 Μm ⁴. After a 25 mg/kg dose of GDC-0084 administered orally, pAKT in normal mouse brain tissue is significantly inhibited at 1 and 6 h postdose. The potent inhibition of pAKT at both time points in this study demonstrates that GDC-0084 inhibits its target behind a fully intact BBB (blood-brain barrier). In addition to the pharmacodynamic effect in normal brain tissue, GDC-0084 is studied in a subcutaneous U87 tumor xenograft model of glioblastoma in mice. In this study, GDC-0084 achieves significant and dose-dependent tumor growth inhibition. Tumor growth inhibition is first observed at a 2.2 mg/kg dose level. Higher doses led to greater tumor growth inhibition, including tumor regressions at the 17.9 mg/kg dose level. Each of these doses is well tolerated for the duration of the study ⁴.

溶解方案(细胞实验)

DMSO 中的溶解度 : 7.69 mg/mL (20.11 mM; 超声助溶 (<60°C); 吸湿的 DMSO 对产品的溶解度有显著影响，请使用新开封的 DMSO)

溶解方案(动物实验)

"方案 一": "请依序添加每种溶剂：10% DMSO 40% PEG300 5% Tween-80 45% SalineSolubility: 1 mg/mL (2.61 mM); 悬浊液; 超声助溶 此方案可获得 1 mg/mL的均匀悬浊液，悬浊液可用于口服和腹腔注射。以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；再向上述体系中加入 50 μL Tween-80，混合均匀；然后再继续加入 450 μL 生理盐水 定容至 1 mL。生理盐水的配制：将 0.9 g 氯化钠，溶解于 ddH₂O 并定容至 100 mL，可以得到澄清透明的生理盐水溶液。"

"方案 二": "请依序添加每种溶剂：10% DMSO 90% (20% SBE-β-CD in Saline)Solubility: 1 mg/mL (2.61 mM); 悬浊液; 超声助溶 此方案可获得 1 mg/mL的均匀悬浊液，悬浊液可用于口服和腹腔注射。以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液 中，混合均匀。2 g SBE-β-CD（磺丁基醚 β-环糊精）粉末定容于 10 mL 的生理盐水中，完全溶解至澄清透明。"

"方案 三": "请依序添加每种溶剂：10% DMSO 90% Corn OilSolubility: ≥ 1 mg/mL (2.61 mM); 澄清溶液 此方案可获得 ≥ 1 mg/mL（饱和度未知）的澄清溶液，此方案实验周期在半个月以上的动物实验酌情使用。以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。"