Three related forms of the kinase Akt (1, 2, 3, also known as protein kinase B isoforms PKBα, β, γ) modulate cell proliferation, metabolism, and survival, as well as angiogenesis. A-674563 is an orally available, ATP-competitive, and reversible inhibitor of Akt (Ki = 11 nM for Akt1). It shows inhibitory activity against PKA and Cdk2 with IC50 values of 16 and 46 nM, respectively, but is 10- to >1,800-fold selective for Akt1 versus additional kinases in the CMGC, CAMK, and TK families. A-674563 reduces phosphorylation of Akt downstream targets in cells and slows proliferation of tumor cells in vitro with an EC50 value of 0.4 μM. In vivo, 40 mg/kg/day A-674563 in combination with 15 mg/kg/day paclitaxel was shown to decrease tumor growth in a PC-3 prostate cancer mouse xenograft model.
