AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM, respectively, exhibiting little activity outside the AGC kinase family.
The protein kinase B (AKT) is a serine/threonine kinase that plays a pivotal role in tumor cell growth, malignant transformation, and chemoresistance. AT7867 is a potent inhibitor of three isoforms of AKT (AKT1, AKT2, and AKT3), the downstream kinase p70S6K, and PKA with IC50 values of 32, 17, 47, 20, and 85nM, respectively. AT7867 potently binds to AK2 in a ATP-competitive manner with a Ki value of 18nM. AT7867 inhibited the proliferation of multiple human cancer cell lines, including MES-SA, MDA-MB-468, MCF-7, U87MG, PC-3, DU145, HCT116, and HT29, with IC50 values in the range of 0.9–12µM. It also exerts an equipotent inhibitory effect on GSK3β phosphorylation across multiple cancer cell lines with IC50 values ranging from 2–4μM. The treatment of U87MG human glioblastoma cells with AT7867 induces apoptosis and suppressed AKT signaling in a concentration- and time-dependent manner. The administration of AT7867 (90mg/kg p.o. or 20mg/kg i.p.) significantly inhibited the phosphorylation of GSK3β and S6RP in mice bearing MES-SA tumors at 2 and 6 h following treatment. Mice treated with AT7867 at 20mg/kg i.p. showed a T/C ratio (tumor volume in treated mice versus control mice) of 0.37 on day 12. The T/C ratio in the group administered with AT7867 at 90mg/kg p.o. was 0.38 on day 10. [2]
作用机制
AT7867 binds to the ATP site of AK2, forming electrostatic interactions with the ribose site, hydrogen-bonding interactions with the kinase hinge region, and hydrophobic contacts with a lipophilic pocket in the glycine-rich loop.[2]
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