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 A-443654

Description of A-443654: A-443654 is a specific Akt inhibitor, which interferes with mitotic progression and bipolar spindle formation. A-443654 induces G(2)/M accumulation, defects in centrosome separation, and formation of either monopolar arrays or disorganized spindles. On the basis of gene expression array studies, we identified Aurora A as one of the genes regulated transcriptionally by Akt inhibitors including A-443654.  Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, either by PI3K inhibitor LY294002 or by A-443654, dramatically inhibits the promoter activity of Aurora A, whereas the mammalian target of rapamycin inhibitor has little effect, suggesting that Akt might be responsible for up-regulating Aurora A for mitotic progression. Further analysis of the Aurora A promoter region indicates that the Ets element but not the Sp1 element is required for A-443654-sensitive transcriptional control of Aurora A. Overexpression of Aurora A in cells treated with A-443654 attenuates the mitotic arrest and the defects in bipolar spindle formation induced by Akt inhibition.  (source: Neoplasia. 2008 Aug;10(8):828-37.)

A443654 is a novel AKT inhibitor,  which leads to rapid cell death of T-ALL lines and patient samples. Treatment of CEM, Jurkat, and MOLT-4 cells with nanomolar doses of the inhibitor led to AKT phosphorylation accompanied by dephosphorylation and activation of the downstream target, glycogen synthase kinase-3beta. Effects were time- and dose-dependent, resulting in apoptotic cell death. Treatment of Jurkat cells with A443654 resulted in activation of caspase-2, -3, -6, -8, and -9. Apoptotic cell death was mostly dependent on caspase-2 activation, as demonstrated by preincubation with a selective pharmacological inhibitor. It is remarkable that A443654 was highly effective against the drug-resistant cell line CEM-VBL100, which expresses 170-kDa P-glycoprotein. Moreover, A443654 synergized with the DNA-damaging agent etoposide in both drug-sensitive and drug-resistant cell lines when coadministered [combination index (CI) = 0.39] or when pretreated with etoposide followed by A443654 (CI = 0.689). The efficacy of A443654 was confirmed using blasts from six patients with T-ALL, all of whom displayed low levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and constitutive phosphorylation of Akt on Ser473. At 1 microM, the inhibitor was able to induce apoptotic cell death of T-ALL blast cells, as indicated by flow cytometric analysis of samples immunostained for active (cleaved) caspase-3. Because activated AKT is seen in a large percentage of patients with T-ALL, A443654, either alone or in combination with existing drugs, may be a useful therapy for primary and drug-resistant T-ALL. See: Mol Pharmacol. 2008 Sep;74(3):884-95. Epub 2008 Jun 24. http://www.ncbi.nlm.nih.gov/pubmed/18577685

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9: Liu X, Shi Y, Woods KW, Hessler P, Kroeger P, Wilsbacher J, Wang J, Wang JY, Li C, Li Q, Rosenberg SH, Giranda VL, Luo Y. Akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression. Neoplasia. 2008 Aug;10(8):828-37. PubMed PMID: 18670641; PubMed Central PMCID: PMC2481570.

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13: Han EK, Leverson JD, McGonigal T, Shah OJ, Woods KW, Hunter T, Giranda VL, Luo Y. Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene. 2007 Aug 16;26(38):5655-61. Epub 2007 Mar 5. PubMed PMID: 17334390.

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