title: A Novel Inhibitor of AKT1-PDPK1 Interaction Efficiently Suppresses the Activity of AKT Pathway and Restricts Tumor Growth In Vivo.
abstract: The serine/threonine kinase AKT/PKB has a critical role in the regulation of cell proliferation. Because AKT signaling is deregulated in numerous human malignancies, it has become an attractive anticancer drug target. A number of small molecule AKT kinase inhibitors have been developed; however, severe side effects have prevented their use in clinical trials. To find inhibitors of AKT1 signaling with principally novel mechanism of action, we carried out a live cell-based screen for small molecule inhibitors of physical interaction between AKT1 and its primary activator PDPK1. The screen revealed one molecule-NSC156529, which downregulated AKT1 signaling, efficiently decreased the proliferation of human cancer cells in vitro, and substantially inhibited the growth of prostate tumor xenografts in vivo. Interestingly, the treated tumor xenografts exhibited higher expression level of normal prostate differentiation markers but did not show augmented cell death, suggesting that the identified compound primarily enhances the differentiation of malignant cells toward normal prostate epithelium and thus poses as an attractive lead compound for developing novel antitumor agents with less cytotoxic side effects.
authors: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. Competence Centre for Cancer Research, Tallinn, Estonia.
authors: Kristina
authors: K
authors: Mäemets-Allas
authors: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. Competence Centre for Cancer Research, Tallinn, Estonia.
authors: Janeli
authors: J
authors: Viil
authors: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. Competence Centre for Cancer Research, Tallinn, Estonia. Karolinska Institutet, Stockholm, Sweden. viljar.jaks@ut.ee.
authors: Viljar
authors: V
authors: Jaks
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C000610390:NSC156529; D054852:Small Molecule Libraries; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D051057:Proto-Oncogene Proteins c-akt