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.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  BT474M1	0.0038-2.5 μM	Function Assay	1 h	induces a dose-dependent increase in Akt phosphorylation at both Thr308 (T308) and Ser473	23287563
  BT474M1	1/5/10 μM	Growth Inhibition Assay	24/48/72 h	dose-dependently increases the G0–G1 phase population	23287563
  BT474M1	1/5/10 μM	Apoptosis Assay	15/48/72 h	causes a dose- and time-dependent increase in apoptotic and necrotic populations	23287563

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• 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

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02390492	Healthy Volunteer	Phase 1	Completed	-	United States, Wisconsin ... more >> Madison, Wisconsin, United States, 53704 Collapse <<
  NCT02063581	Healthy Volunteer	Phase 1	Completed	-	United States, Wisconsin ... more >> Madison, Wisconsin, United States, 53704 Collapse <<
  NCT02430363	Glioblastoma	Phase 1 Phase 2	Unknown	June 2018	United States, Massachusetts ... more >> Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, Texas M D Anderson Cancer Center Houston, Texas, United States, 77030 Belgium UCL- Cliniques Universitaires Saint Luc Brussels, Belgium Germany St Johannes Hospital Duisburg, Germany, 47166 Italy Spedali Civili di Brescia Brescia, Italy IRCCS San Raffaele Milan, Italy Poland Lower-Silesian Oncology Centre Wroclaw, Lower-Silesian, Poland, 53413 Russian Federation Pavlov State Medical University St. Petersburg, Russian Federation, 197089 Spain Hospital Universitario Germans Trias I Pujol Barcelona,, Spain Switzerland Universitätsklinik für Frauenheilkunde Bern, Switzerland Ukraine Regional Cancer Center Dnepropetrovsk, Ukraine, 49000 National Institute of Cancer Kiev, Ukraine, 03035 United Kingdom Royal Victoria Hospital Belfast, Ulster, United Kingdom, BT12 6BA Collapse <<

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• 参考文献

• [1] Huck BR, Mochalkin I, et al. Recent progress towards clinically relevant ATP-competitive Akt inhibitors. Bioorg Med Chem Lett. 2017 Jul 1;27(13):2838-2848.

  [2] Blake JF, Xu R, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012 Sep 27;55(18):8110-27. Epub 2012 Sep 18.

  [3] Lin J, Sampath D, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72.

  [4] EP2928488A1