生物活性

• 描述Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. 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. 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. 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.
• 作用机制GDC-0084 is a brain penetrant inhibitor of PI3K and mTOR.