Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1

被引:181
作者
Feldman, RI
Wu, JM
Polokoff, MA
Kochanny, MJ
Dinter, H
Zhu, DG
Biroc, SL
Alicke, B
Bryant, J
Yuan, SD
Buckman, BO
Lentz, D
Ferrer, M
Whitlow, M
Adler, M
Finster, S
Chang, Z
Arnaiz, DO
机构
[1] Berlex Biosci, Dept Canc Res, Richmond, CA 94804 USA
[2] Berlex Biosci, Dept Pharmacol, Richmond, CA 94804 USA
[3] Berlex Biosci, Dept Chem, Richmond, CA 94804 USA
[4] Berlex Biosci, Dept Syst Biol, Richmond, CA 94804 USA
关键词
D O I
10.1074/jbc.M501367200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:19867 / 19874
页数:8
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