1. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo
- Author
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Amanda K Mika, Eric F. Johnson, Joel D. Leverson, Keith W. Woods, Michael J. Mitten, Jennifer J. Bouska, Xuesong Liu, Bradley A. Zinker, Thomas McGonigal, Richard A. Smith, Saul H. Rosenberg, Tongmei Li, Mulugeta Mamo, Anatol Oleksijew, Ron De Jong, Tilman Oltersdorf, Vincent S. Stoll, Emily E. Gramling-Evans, Alexander R. Shoemaker, Yan Luo, Vered Klinghofer, Phong T. Nguyen, Jessica A. Powlas, Sheela A. Thomas, Yan Shi, Qun Li, Ran Guan, Edward K. Han, and Vincent L. Giranda
- Subjects
Models, Molecular ,Cancer Research ,Indazoles ,Indoles ,Pyridines ,AKT1 ,Antineoplastic Agents ,Mice, SCID ,Protein Serine-Threonine Kinases ,Pharmacology ,Carbohydrate metabolism ,Biology ,Sensitivity and Specificity ,Substrate Specificity ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Neoplasms ,Proto-Oncogene Proteins ,Animals ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,Protein kinase B ,Kinase ,Protein Structure, Tertiary ,Oncology ,Paclitaxel ,chemistry ,Tumor progression ,Disease Progression ,Signal transduction ,Proto-Oncogene Proteins c-akt - Abstract
The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (Ki = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses ∼2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.
- Published
- 2005
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