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-443654 is an inhibitor of Akt (Ki = 160 pmol/L for all three isoforms) that interferes with mitotic progression and bipolar spindle formation. It induces G2/M accumulation, defects in centrosome separation, and formation of either monopolar arrays or disorganized spindles. A-443654 has been reported to slow the progression of Akt-dependent tumors in in vivo mouse models. In response to an A-443654-induced decrease in phosphorylation of Akt targets, a concomitant increase in Thr308 and Ser473 phosphorylation of Akt has been observed in human cancer cell lines. A-443654 has been used to examine the mechanism of this rapid feedback reaction.
