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

作者：Richard I. Feldman, James M. Wu, Mark A. Polokoff, Monica J. Kochanny, Harald Dinter, Daguang Zhu, Sandra Lyn Biroc, Bruno Alicke, Judi A. Bryant, Shendong Yuan, Brad O. Buckman, Dao Lentz, Mike Ferrer, Marc D. Whitlow, Marc Adler, Silke Finster, Zheng Chang, Damian O. Arnaiz · 发表于：Journal of Biological Chemistry · 年份：2005 · DOI：10.1074/jbc.m501367200 · 被引用次数：231 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Cancer Mechanisms and Therapy、Ubiquitin and proteasome pathways

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.