生物活性

• 靶点

  Akt1 IC50:180nM

  Akt2 IC50:328nM

  Akt3 IC50:38nM

• 描述AKT is the central node of the PI3K/AKT/ mTOR pathway. The PH domain and ATP-competitive site are the main target site for research of new compound^[2]. GSK2141795 is an ATP-competitive pan AKT inhibitor with Ki values of 180, 328 and 38nM for AKT 1, 2 and 3 (determined by the kinobead competition binding assay)^[1]. Treatment of GSK2141795 on concentration of 1-10 μM can induce G1-arrest and decrease the phosphorylation level of multiple AKT substrate including PRAS40, FOXO and Caspase 9 in BT474 and LNCaP cell lines in a concentration-dependent manner, accompanied by feedback increase in AKT phosphorylation. In cell growth inhibition study, overall 81% of the hematological cell lines were sensitive to GSK2141795 (EC50 <1 uM). Among solid tumor cell lines, 36% had EC50<1 μM in response to GSK2141795. Cell lines containing activating mutations to KRAS, NRAS or BRAF showed more resistence to GSK2141795. Mice bearing SKOV3 ovarian tumor xenografts orally treated with 10, 20 and 30 mg/kg GSK2141795, once daily for 21 days, displayed a 73, 85 or 93% TGI, respectively^[3]. Several clinical trials of GSK2141795, including a phase 1 study of GSK2141795 of treatment for solid tumors, have been completed (see in https://clinicaltrials.gov/).
• 作用机制GSK2141795 is an ATP-competitive AKT inhibitor.
• 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
  NCT02093546	-	-	Active, not recruiting	August 31, 2019	United States, Texas ... more >> M D Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT01138085	Cancer	Phase 1	Completed	-	United States, Colorado ... more >> GSK Investigational Site Aurora, Colorado, United States, 80045 United States, Connecticut GSK Investigational Site New Haven, Connecticut, United States, 06520 United States, Massachusetts GSK Investigational Site Boston, Massachusetts, United States, 02114 GSK Investigational Site Boston, Massachusetts, United States, 02215 United States, New Jersey GSK Investigational Site New Brunswick, New Jersey, United States, 08901 United States, Tennessee GSK Investigational Site Nashville, Tennessee, United States, 37232 United States, Texas GSK Investigational Site Dallas, Texas, United States, 75246 GSK Investigational Site Houston, Texas, United States, 77230-1439 GSK Investigational Site San Antonio, Texas, United States, 78229 United States, Utah GSK Investigational Site Salt Lake City, Utah, United States, 84112-5550 Collapse <<
  NCT01979523	Recurrent Uveal Melanoma ... more >> Stage IV Uveal Melanoma AJCC v7 Collapse <<	Phase 2	Completed	-	United States, Georgia ... more >> Emory University Hospital/Winship Cancer Institute Atlanta, Georgia, United States, 30322 United States, New York Columbia University/Herbert Irving Cancer Center New York, New York, United States, 10032 Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10065 United States, Tennessee Vanderbilt University/Ingram Cancer Center Nashville, Tennessee, United States, 37232 United States, Texas M D Anderson Cancer Center Houston, Texas, United States, 77030 France Institut Curie Paris Paris, France, 75005 United Kingdom The University of Liverpool Liverpool, United Kingdom, L69 3GA Collapse <<

• 更多
• 参考文献

• [1] Pachl F, Plattner P, et al. Characterization of a chemical affinity probe targeting Akt kinases. J Proteome Res. 2013 Aug 2;12(8):3792-800.

  [2] 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.

  [3] Dumble M, Crouthamel MC, et al. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014 Jun 30;9(6):e100880.