GDC-mTOR inhibitor 是一种具有显着选择性的 mTOR 抑制剂，Ki 为 1.5 nM。 GDC-mTOR inhibitor 在细胞和体内药代动力学 (PK)/药效学 (PD) 实验中抑制 mTORC1 和 mTORC2。
Animal experiment: | Mice[2]Human prostate cancer NCI-PC3 cells are implanted subcutaneously into the right hind flanks of female NCR nude mice (5×106 cells in 100 μL of Hank’s balanced salt solution). Tumors are monitored until they reach a mean tumor volume of approximately 500 mm3. Then similarly sized tumors are randomly assigned to groups (n=4). Compounds are formulated as suspensions in 0.5% methylcellulose/0.2% Tween 80 (MCT) and dosed orally at 25, 50, and 100 mg/kg (100 μL dose/25 g animal). Tumor and plasma samples are harvested at 1, 6, and 10 h postdose. |
| 产品描述 | Description:
IC50 Value: 1.5nM (Ki)
GDC-mTOR inhibitor is a potent and selective ATP-competitive inhibitor of mTOR. It's derivative drug, GDC-0349, demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.
Abstract: Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with Ki < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study. |
