生物活性

• 靶点

  mTORC1 Ki:0.18nM

  mTORC2 Ki:0.3nM

  p110α Ki:0.019nM

  p110β Ki:0.13nM

  p110γ Ki:0.06nM

  更多

• 描述PI3K/AKT/mTOR pathway directly relates to cellular quiescence, proliferation, cancer, and longevity. There are eight PI3 kinases have been identified as classes IA, 1B, II, and III based on the sequence homology and substrate preference. Among them, class IA PI3K is composed of a heterodimer consisting of a 110 kDa catalytic subunit (p110α, p110β and p110δ) and an 85 kDa regulatory subunit^[1]. GSK2126458 (Omipalisib,GSK458) is a dual PI3K/mtor inhibitor, of which Ki value on p110α/β/δ/γ, mTORC1/2 is 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM measured by HTRF In vitro Profiling Assays, respectively. In cell study, GSK2126458 caused a significant reduction in the levels of pAKT-S473, pAKT-T308 and p70S6K at low nanomolar concentrations, as well as induced a G1 cell cycle arrest and inhibited cell proliferation in a large panel of cell lines, such as T47D and BT474 breast cancer lines. GSK2126458 shows both good pharmacokinetic and pharmacodynamic properties. In animal study, it showed low blood clearance and good oral bioavailability. A single 300 μg/kg dose of GSK2126458 exhibited a dose-dependent reduction in pAKT-S473 levels in BT474 tumors implanted in mice, while five times per week for 3 weeks of oral treatment of GSK2126458 exhibited dose-dependent tumor growth inhibition^[2]. Up to now, GSK2126458 is being tested in a phase I study in subjects with solid tumors or lymphoma^[3].
• 作用机制GSK2126458 bounded in the ATP-binding site of the PI3K^[2].

• 动物研究
  剂量	Mice (p.o.): min = 0.3 mg/kg[2], max = 3 mg/kg[4]
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Rats[2] Dogs[2] Monkeys[2] T1/2 2.1 h 6.2 h 1.3 h 3.5 h DNAUC 1100 ng·h/ml/mg/kg 6100 ng·h/ml/mg/kg 2400 ng·h/ml/mg/kg 2300 ng·h/ml/mg/kg Vdss 1.0 L/kg 1.1 L/kg 0.7 L/kg 0.8 L/kg F 1 0.81 0.8 0.49 CL 10 ml/min/kg 2.3 ml/min/kg 5.8 ml/min/kg 3.6 ml/min/kg

• 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
  NCT01725139	Idiopathic Pulmonary Fibrosis	Phase 1	Completed	-	United Kingdom ... more >> GSK Investigational Site London, United Kingdom, SW3 6NP Collapse <<
  NCT00972686	Solid Tumours	Phase 1	Completed	-	United States, California ... more >> GSK Investigational Site San Francisco, California, United States, 94115 United States, New Jersey GSK Investigational Site New Brunswick, New Jersey, United States, 08901 United States, North Carolina GSK Investigational Site Chapel Hill, North Carolina, United States, 27599-7600 United States, Texas GSK Investigational Site Dallas, Texas, United States, 75246 GSK Investigational Site Houston, Texas, United States, 77030 United States, Utah GSK Investigational Site Salt Lake City, Utah, United States, 84112-5550 United States, Washington GSK Investigational Site Seattle, Washington, United States, 98109 Netherlands GSK Investigational Site Amsterdam, Netherlands, 1066 CX GSK Investigational Site Utrecht, Netherlands, 3584 CX Collapse <<
  NCT01248858	Cancer	Phase 1	Terminated(The reason for term... more >>ination was lack of tolerability and efficacy of the combination treatment) Collapse <<	-	United States, North Carolina ... more >> GSK Investigational Site Chapel Hill, North Carolina, United States, 27599-7305 United States, Tennessee GSK Investigational Site Nashville, Tennessee, United States, 37203 Canada, Ontario GSK Investigational Site Toronto, Ontario, Canada, M5G 2M9 Italy GSK Investigational Site Milano, Lombardia, Italy, 20132 Collapse <<

• 参考文献

• [1] Zhao HF, Wang J, et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer. 2017 Jun 7;16(1):100.

  [2] Knight SD, Adams ND, et al. Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett. 2010 Jan 19;1(1):39-43.

  [3] Schenone S, Brullo C, et al. ATP-competitive inhibitors of mTOR: an update. Curr Med Chem. 2011;18(20):2995-3014.

  [4] Ma J, Sun Y, et al. Blockage of PI3K/mTOR Pathways Inhibits Laser-Induced Choroidal Neovascularization and Improves Outcomes Relative to VEGF-A Suppression Alone. Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):3138-44.