A-443654

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 (K_i = 160 pmol/L for all three isoforms) that interferes with mitotic progression and bipolar spindle formation.^1,2 It induces G₂/M accumulation, defects in centrosome separation, and formation of either monopolar arrays or disorganized spindles.² A-443654 has been reported to slow the progression of Akt-dependent tumors in in vivo mouse models.¹ 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.³ A-443654 has been used to examine the mechanism of this rapid feedback reaction.

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1. Luo, Y., Shoemaker, A.R., Liu, X., et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol. Cancer Ther. 4(6), 977-968 (2005).

2. Liu, X., Shi, Y., Woods, K.W., et al. Akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression. Neoplasia 10(8), 828-837 (2008).

3. Han, E.K., Leverson, J.D., McGonigal, T., et al. Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene 26(38), 5655-5661 (2007).