生物活性

• 靶点

  Akt1 IC50:5nM

  Akt2 IC50:18nM

  Akt3 IC50:8nM

• 描述AKT is the central node of PI3K/AKT/mTOR pathway. The PH domain and ATP-competitive site are the main target site for research of new compound^[1]. GDC-0068 (Ipatasertib) is an ATP-competitive pan Akt inhibitor with IC50 values of 5 nM, 18 nM and 8 nM on AKT 1, 2 and 3 isoforms, respectively^[2]. Treatment of GDC-0068 on concentration of 0.1 - 25 μM caused decreased phosphorylation of the downstream targets of AKT, such as FoxO1 and FoxO3a, 4EBP1 and S6 in a dose- and time-dependent manner in PC-3, BT474M1, and IGROV-1 cell lines, accompanied by feedback increase in AKT phosphorylation. Treatment of GDC-0068 on concentration of 1 – 10 μM can induce G1-arrest (including in PC-3 cells) and increase in apoptotic and necrotic populations in a dose- and time-dependent manner in BT474M1 and MCF7-neo/HER2 cells, but not in PC-3 cells. In growth inhibition assay, cell lines with high Akt activity show more sensitivity to GDC-0068. GDC-0068 showed good pharmacokinetics and pharmacodynamics in xenograft models. The level of pPRAS40-T246 in LNCaP tumors at 1 and 4 hours after a single dose of GDC-0068 at 12.5, 25, 50, or 100 mg/kg decreased in a dose-dependent manner. GDC-0068 on dose of 50 mg/kg in combination with docetaxel induced tumor regression and stasis in the PC-3 and MCF7-neo/HER2 xenograft models^[3]. The clinical trials of GDC-0068, including a completed phase 2 study of combination with paclitaxel as neoadjuvant treatment for participants with early stage triple negative breast cancer, have been done (see in https://clinicaltrials.gov/).
• 作用机制GDC-0068 is an ATP-competitive AKT inhibitor.

• 动物研究
  剂量	Mice: min = 40 mg/kg[4] (s.c.), max = 100 mg/kg[3] (p.o.)
  给药途径	s.c., p.o.
  动物药代数据	Animal Mice[3] Cmax 4-8 h