中文名称:
4-(4-氯苯基)-4-[4-(1H-吡唑-4-基)苯基]哌啶二盐酸盐
中文同义词:
4-(4-氯苯基)-4-[4-(1H-吡唑-4-基)苯基]哌啶二盐酸盐;AKT1/AKT2/AKT3和P70S6K/PKA抑制剂(AT7867 DIHYDROCHLORIDE)
英文名称:
AT 7867 dihydrochloride
英文同义词:
AT 7867 dihydrochloride;AT7867 (dihydrochloride);AT-7867 dihydrochloride;4-(4-Chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine hydrochloride (1:2);AT7867 2HCl;AT-7867 DIHYDROCHLORIDE;AT 7867 DIHYDROCHLORIDE
生物活性
AT7867 dihydrochloride 是一种 ATP 竞争性的 Akt1/Akt2/Akt3 和 p70S6K/PKA 抑制剂，IC50 分别为 32 nM/17 nM/47 nM 和 85 nM/20 nM。
靶点
Akt1
32 nM (IC 50 )
Akt2
17 nM (IC 50 )
Akt3
47 nM (IC 50 )
PKA
20 nM (IC 50 )
Akt1
32 nM (IC 50 )
Akt2
17 nM (IC 50 )
体外研究
The inhibition of AKT2 by AT7867 is shown to be ATP-competitive with a K i of 18nM. AT7867 also displays potent activity against the structurally related AGC kinases p70S6K and PKA, but shows a clear window of selectivity against kinases from other kinase sub-families. In vitro growth inhibition studies show that AT7867 blocks proliferation in a number of human cancer cell lines. AT7867 appears to be most potent at inhibiting proliferation in MES-SA uterine, MDA-MB-468 and MCF-7 breast, and HCT116 and HT29 colon lines (IC 50 values range from 0.9-3 μM), and least effective in the two prostate lines tested (IC 50 values range from 10-12 μM) .
体内研究
Following oral administration at 20 mg/kg, the elimination of AT7867 from plasma appears to be similar to that observed after i.v. administration. Plasma levels of AT7867 remain above 0.5 μM for at least 6 hours following an oral dose of 20 mg/kg. Assuming linear pharmacokinetics following i.v. administration, the bioavailability by the oral route is calculated to be 44%. In vivo pharmacodynamic (PD) biomarker studies are therefore performed with this model. Following pharmacokinetic and tolerability studies, doses of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) are administered to athymic mice bearing MES-SA tumors and the phosphorylation status of GSK3β and S6RP in tumors is monitored over time. Clear inhibition of phosphorylation of the two markers of pathway activity is seen at 2 and 6 hours following treatment with AT7867. By 24 hours, total levels of both GSK3β and S6RP are greatly reduced.
