生物活性

• 靶点

  ATR IC50:21nM

  mTOR(p70S6K) IC50:6nM

  p110α IC50:4nM

  p110β IC50:75nM

  p110γ IC50:5nM

  更多

• 描述Aberrant activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) signaling pathway promotes the proliferation and survival of various human tumor cells. BEZ235 is a ATP competitive inhibitor of PI3K that inhibits the kinase activity of Class I PI3K p110α/β/δ/γ with IC50 of 4 nM, 75 nM, 7 nM, and 5 nM, respectively. In U87MG glioblastoma cells, the exposure of 0.1 - 1000 nM BEZ235 for 30 min reduced S473P-Akt and T308P-Akt levels in a dose-dependent manner, and the 50% reduction occurred at the doses of 8 nM and 30 nM, respectively. In NWT21 cells, pretreatment of 250 nM BEZ235 reduced insulin-like growth factor-I-induced S473P-Akt level. In starved HT-29 cells, BEZ235 at 250 nM efficiently inhibited interleukin-4-induced S473P-Akt level. The phosphorylation level of mTOR activated kinase p70^S6K was significantly reduced by 250 nM BEZ235 in U87MG cells after 30 min incubation. The S235/S236P-RPS6 level in TSC1-null MEF cells was decreased by BEZ235 with an IC50 of 6.5 nM. The addition of BEZ235 (5 - 500 nM) dose-dependently downregulated mTORC1 and mTORC2 activities in IgG-Sepharose pull-downs of HeLa cells. BEZ235 also showed inhibitory effect on cell proliferation. The G_{1 population of PC3M cells was increased from 66.4% to 74.1% and 92.3% after the treatment with 10 nM and 50 nM BEZ235, respectively. In U87MG tumor-bearing mice, treatment of BEZ235 (25 – 45 mg/kg/d, once daily) for 20 days inhibited tumor growth and reduced S473P-Akt levels in the tumor at a dose-dependent manner^[3].}
• 作用机制BEZ235 inhibits PI3K via binding to its ATP-binding cleft^[3].

• 动物研究
  剂量	Mice[3] (p.o.): min = 1 mg/kg, max = 50 mg/kg
  给药途径	p.o.