生物活性

• 描述The phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway is one of the most frequently dysregulated signaling cascades in human malignancies, it displays oncogenic potential and it is implicated in a wide variety of different neoplasms. NVP-BGT226 (BGT226), an imidazoquinoline derivative, an ATP-competitive dual PI3K/mTORC1/C2 inhibitor: it is a potent pan-class I PI3K inhibitor (p110α, β, δ, and γ, with a preference for the α-isoform -wild type and mutated-) and is a mTORC1/2 catalytic inhibitor. The IC50s of NVP-BGT226 is 4 nM, 63 nM and 38 nM for PI3Kα, PI3Kβ and PI3Kγ. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition. There is extensive crosstalk between the two signalling networks. mTOR can affect PI3K/Akt signalling through the S6K-IRS1 feedback loop and induce Akt phosphorylation by mTORC2. NVP-BGT226 can effectively block downstream targets and result in radiation sensitization in tumor cell lines and in endothelial cells. BGT226 could affect the viability of HCC cell lines, Mahlavu, SNU475, SNU449, HepG2 and Hep3B cells when they were incubated in the presence of increasing concentrations of the drug from 0.50 μM to 1.5 μM for either 24 or 48h. The experiments documented that already at 24h all the cell lines were very sensitive to BGT226. After 48h of treatment cell viability impairment was more evident, with an IC50 value ranging from 0.55 μM for Mahlavu to 1.35 μM for HepG2 cell. Oral administration of BGT226 at 2.5 and 5 mg/kg for 3 weeks caused 34.7% and 76.1% reduction of the tumor growth in the human FaDu xenografted mice on day 21, respectively (compared with control).

• 动物研究
  剂量	BALB/c mice: 4 mg/kg, 8mg/kg[3] (p.o.), 2.5 mg/kg - 5 mg/kg[4] (p.o.)
  给药途径	p.o.