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