生物活性

• 靶点

  Akt1 IC50:2nM

  Akt2 IC50:13nM

  Akt3 IC50:9nM

• 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]. GSK690693 is an ATP-competitive pan AKT inhibitor with IC50 values of 2, 13 and 9nM for AKT 1, 2, and 3, respectively. Treatment with GSK690693 on concentration of 0.01-10uM cause decreased phosphorylation level of GSK3, p70S6K, and PRAS40 in BT474 breast tumor cells in a dose-dependent manner. GSK690693 can induce accumulation of the FOXO3A, an Akt downstream substrate, in the nucleus at concentration >1uM. In growth inhibition studies, cell lines with higher level of p-AKT showed more sensitivity to GSK690693, such as HCC1954, ZR-75-1, BT474 and LNCaP, etc.. In vivo studies showed maximal tumor growth inhibition of 58% to 75% at the end of dosing period with 30mg/kg/day dose of GSK690693 (i.p.) for 21 days in mice bearing established SKOV-3 ovarian, LNCaP prostate, BT474 and HCC-1954 breast carcinoma xenografts^[2].
• 作用机制GSK690693 is an ATP-competitive AKT inhibitor^[2].

• 动物研究
  剂量	Mice[3]: 30 mg/kg (i.p,)
  给药途径	i.p.
  动物药代数据	Animal Rats[4] Dogs[4] Monkeys Dose 10.6 mg/kg 4.2 mg/kg 4.3 mg/kg Administration i.v. i.v. i.v. Cmax 2.13 ± 0.19 μg/ml 1.30 ± 0.11 μg/ml 1.50 ± 0.10 μg/ml T1/2 8.92 ± 1.03 h 3.50 ± 0.33 h 5.52 ± 0.43 h Protein binding (free drug %) j AUC0→t 3.15 ± 0.32 (μg·h)/ml (0-inf) 2.01 ± 0.11 (μg·h)/ml (0-inf) 3.25 ± 0.67 (μg·h)/ml (0-inf) CL 56.7 ± 5.5 (ml·min)/kg 34.6 ± 2.0 (ml·min)/kg 22.5 ± 4.3 (ml·min)/kg Vss 15.2 ± 1.3 L/kg 5.29 ± 0.24 L/kg 6.54 ± 0.89 L/kg