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[2]. Afuresertib （GSK2110183） is an ATP-competitive inhibitor of AKT1/2/3 with Ki value of 0.08nM, 2nM and 2.6nM (measured by a filter binding assay), respectively. Treatment of Afuresertib on concentration of 1-10uM can induce G1-arrest and decrease the phosphorylation level of multiple AKT substrate including PRAS40, FOXO and Caspase 9 in BT474 and LNCaP cell lines in a concentration-dependent manner, accompanied by feedback increase in AKT phosphorylation. Afuresertib has more potent anti-proliferative effects on a variety of hematological malignancies (65% were sensitive to Afuresertib with EC50<1uM)). Among solid tumor cell lines, 21% had EC50<1uM in response to Afuresertib. Treatment with Afuresertib at 10, 30 and 100mg/kg, daily for 7 days, can decrease PRAS40 phosphorylation by 8%, 37% and 61% in mice bearing BT474 tumors, which showed the good pharmacodynamics of Afuresertib[1]. Single-agent Afuresertib shows clinical activity against hematologic malignancies, including multiple myeloma[3].
作用机制
Afuresertib is an ATP-competitive AKT inhibitor.[1]
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