Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1
| Autor: | Dao Lentz, Marc Whitlow, Zheng Chang, Harald Dinter, Mike Ferrer, Silke Finster, Marc Adler, Daguang Zhu, Sandra L. Biroc, Richard I. Feldman, Bruno Alicke, Monica Kochanny, Judi Bryant, Brad O. Buckman, Mark A. Polokoff, Arnaiz Damian O, James M. Wu, Shendong Yuan |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Lung Neoplasms animal structures Drug Evaluation Preclinical Melanoma Experimental Mice Nude Antineoplastic Agents In Vitro Techniques Protein Serine-Threonine Kinases Biology Biochemistry 3-Phosphoinositide-Dependent Protein Kinases Mice chemistry.chemical_compound Catalytic Domain Cell Line Tumor Proto-Oncogene Proteins Animals Humans Protein Kinase Inhibitors Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Molecular Structure Kinase Akt/PKB signaling pathway Cell Biology Xenograft Model Antitumor Assays Cell biology Kinetics Pyrimidines chemistry Cell culture Cancer cell Female Growth inhibition Proto-Oncogene Proteins c-akt Cell Division HeLa Cells Signal Transduction Phosphoinositide-dependent kinase-1 |
| Zdroj: | Journal of Biological Chemistry. 280:19867-19874 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m501367200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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