Abstract
Accumulated studies have shown that activation of the Akt pathway plays a pivotal role in malignant transformation and chemoresistance by inducing cell survival, growth, migration, and angiogenesis. Therefore, Akt is believed to be a critical target for cancer intervention. Here, we report the discovery of a small molecule Akt pathway inhibitor, Akt/protein kinase B signaling inhibitor-2 (API-2), by screening the National Cancer Institute Diversity Set. API-2 suppressed the kinase activity and phosphorylation level of Akt. The inhibition of Akt kinase resulted in suppression of cell growth and induction of apoptosis in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. API-2 is highly selective for Akt and does not inhibit the activation of phosphatidylinositol 3'-kinase, phosphoinositide-dependent kinase-1, protein kinase C, serum- and glucocorticoid-inducible kinase, protein kinase A, signal transducer and activators of transcription 3, extracellular signal-regulated kinase-1/2, or c-Jun NH(2)-terminal kinase. Furthermore, API-2 potently inhibited tumor growth in nude mice of human cancer cells in which Akt is aberrantly expressed/activated but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting Akt for anticancer drug discovery.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Division / drug effects
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Cell Line, Tumor
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Enzyme Inhibitors / pharmacology*
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Female
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Humans
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Immediate-Early Proteins
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Signaling System / drug effects
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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NIH 3T3 Cells
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Nuclear Proteins*
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Nucleosides / pharmacology*
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Protein Kinase C / antagonists & inhibitors
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Pyridazines / pharmacology*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Substrate Specificity
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Xenograft Model Antitumor Assays
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p38 Mitogen-Activated Protein Kinases
Substances
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API-2 nucleoside
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Enzyme Inhibitors
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Immediate-Early Proteins
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Nuclear Proteins
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Nucleosides
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Proto-Oncogene Proteins
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Pyridazines
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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serum-glucocorticoid regulated kinase
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases