AT7867

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

AT7867 是一种有效的 ATP 竞争性口服双重 Akt 和 p70S6K 抑制剂，Ki 为 17-85 nM，也能抑制 PKA，Ki 为 20 nM。

AT7867 is a potent, ATP-competitive, orally available dual Akt and p70S6K inhibitor with Ki of 17-85 nM, also inhibits PKA with Ki of 20 nM; potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3beta (IC50=7.1 uM, pSer9 GSK3β in U87MG glioblastoma cells) and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines; inhibits AKT and p70S6K and induces apoptosis, inhibits human tumor growth in PTEN-deficient xenograft models.

The inhibition of AKT2 by AT7867 is shown to be ATP-competitive with a Ki 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 (IC50 values range from 0.9-3 μM), and least effective in the two prostate lines tested (IC50 values range from 10-12 μM) .

In vivo: 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.

AT-7867 | AT 7867

Cytoskeleton/Cell Adhesion Molecules

Akt

Akt1| Akt2| Akt3| PKA| p70 S6K

Cancer

——

857531-00-1

337.8459

C20H20ClN3

>98% (HPLC)

10 mM in DMSO

ClC1=CC=C(C=C1)C2(CCNCC2)C3=CC=C(C=C3)C4=CNN=C4

Piperidine, 4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]-

(-20℃)

With Ice Pack

≥ 2 years