Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1

• Published in: The Journal of biological chemistry 2005-05, Vol.280 (20), p.19867-19874
• Main Authors: Feldman, Richard I., Wu, James M., Polokoff, Mark A., Kochanny, Monica J., Dinter, Harald, Zhu, Daguang, Biroc, Sandra L., Alicke, Bruno, Bryant, Judi, Yuan, Shendong, Buckman, Brad O., Lentz, Dao, Ferrer, Mike, Whitlow, Marc, Adler, Marc, Finster, Silke, Chang, Zheng, Arnaiz, Damian O.
• Format: Article
• Language: English
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Catalytic Domain; Cell Division - drug effects; Cell Line, Tumor; Drug Evaluation, Preclinical; Female; HeLa Cells; Humans; In Vitro Techniques; Kinetics; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Melanoma, Experimental - secondary; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Pyrimidines - chemistry; Pyrimidines - pharmacology; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M501367200

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 (IC50 = 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.