A small molecule compound selectively inhibits Akt, including AKT1-E17K, signaling and tumor growth in cancer cells with hyperactivated Akt

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The serine/threonine kinase Akt/PKB¹ pathway is frequently hyperactivated in human cancer and functions as a cardinal nodal point for transducing extracellular and intracellular oncogenic signals, and thus presents an exciting target for molecular therapeutics. Here, we reported the identification of a small molecule Akt inhibitor, AKT-SI (Akt signaling inhibitor)-1. AKT-SI1 treatment of cancer cells results in inhibition of the kinase activities and phosphorylation levels of the three members of Akt family. In contrast, AKT-SI1 had no effects on the activities of the upstream Akt activators, PI3K and PDK1. Significantly, the kinase activity and phosphorylation (e.g., pT308 and pS473) levels of constitutively active Akt, including a naturally occurring mutant AKT1-E17K that resists to an allosteric Akt kinase inhibitor, were potently inhibited by AKT-SI1. AKT-SI1 is highlyselective for Akt and does not inhibit the activation of PKC, SGK, PKA, STAT3, Erk-1/2, or JNK. The inhibition of Akt by AKT-SI1 resulted in induction of cell growth arrest and apoptosis selectively in human cancer cells that harbor constitutively activated Akt. Significantly, AKT-SI1 inhibited tumor growth in nude mice of human cancer cells in which Akt is elevated but not of those cancer cells in which it is not. These data indicate that AKT-SI1 is an Akt pathway inhibitor with anti-tumor activity in vitro and in vivo and could be a potential anti-cancer agent for patients whose tumors express hyperactivated Akt.