Abstract
The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Catalytic Domain
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Cell Division / drug effects
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Cell Line, Tumor
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Drug Evaluation, Preclinical
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Female
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HeLa Cells
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Humans
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In Vitro Techniques
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Kinetics
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Lung Neoplasms / secondary
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / pathology
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Melanoma, Experimental / secondary
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Mice
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Mice, Nude
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrimidines
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3-Phosphoinositide-Dependent Protein Kinases
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AKT1 protein, human
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PDPK1 protein, human
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Pdpk1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt