生物活性

• 靶点

  PI3Kα IC50:0.29nM

  PI3Kγ IC50:0.97nM

  PI3Kδ IC50:0.12nM

• 描述Phosphoinositide-3 kinase (PI3K) plays important role in response to various extracellular triggers and in activation of downstream Akt and mTOR, which together control the tumor cell proliferation. GDC-0032 is the inhibitor of PI3K with Ki of 0.29 nM for PI3Kα, with IC₅₀ values of 4.0 nM and 25 nM for p-Akt and MCF7-neo/HER2 cell lines respectively. In MCF7-neo/Her2 xenograft model, treatment of GDC-0032 with concentrations ranging from 1.4 to 22.5 mg/kg resulted in an increasing of tumor growth inhibition with corresponding inhibition rates from 19% to 123%, dose-dependently. Akt phosphorylation was also decreased by 59% when treated with 2.8 mg/kg of GDC-0032. In a panel containing 235 kinases, treated them with 1 μM GDC-0032 led to >70% inhibition in PI3K-C2 beta, PI3Kα, PI3Kδ, PI3Kγ and hVPS34. The IC₅₀ values for PI3K-C2 beta and hVPS34 were 292 nM and 374 nM, respectively^[1]. In a panel of 26 HNSCC cell lines, GDC-0032 showed gradient inhibition IC₅₀ values ranging from 0.05 to 2 μM. The 4 cell lines with IC₅₀ values 2 μM are most resistant to GDC-0032 due to the mutation or loss of PTEN gene. In Cal-33 cells harboring a PIK3CA H1047R mutation, treatment of GDC-0032 with concentrations ranging from 0 to 4 μM prevented AKT phosphorylation and inhibited S6 kinase level, leading to an induction of apoptosis. However, less effect on AKT/mTOR signaling in cell lines containing PTEN mutations was also observed, which means that GDC-0032 only inhibits PI3Kα-dependent signaling. Also in Cal-33 cells, the combination treatment of GDC-0032 and radiation led to more apoptotic, more non-apoptotic cell death and slower cell growth rates. In Cal-33 xenografts mice model with 5 mg/kg of GDC-0032, AKT and PRAS40 phosphorylation were almost completely abrogated as well as the decreasing of 4EBP-1 and S6 phosphorylation at 2 hours treatment. The treatment also mildly improved the proportion of cells in G1 phase and decreased G2 phase of the cell cycle over 72 hours^[2].

• 动物研究
  剂量	Mice: 0.2 mg/kg - 25 mg/kg[3] (p.o.)
  给药途径	p.o.