Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines.
Recent evidence suggests that the machinery of protein synthesis may provide novel targets for anticancer drugs. For example, aberrations in protein synthesis are commonly encountered in established cancers, and disruption by mutation or overexpression of translation factors can cause cellular transformation. We previously demonstrated that the activity of eukaryotic elongation factor 2 (eEF-2) kinase was markedly increased in several forms of malignancy and that nonspecific inhibitors of this enzyme promoted cell death. On the basis of the predicted amino acid sequence of eEF-2 kinase deduced from the cloned cDNA, we hypothesized that inhibitors of prokaryotic histidine kinases might also inhibit the activity of eEF-2 kinase. We describe herein the screening of a series of imidazolium histidine kinase inhibitors and the identification of an active lead compound, NH125. NH125 inhibited eEF-2 kinase activity (IC(50) = 60 nM) in vitro, blocked the phosphorylation of eEF-2 in intact cells, and showed relative selectivity over other protein kinases: protein kinase C (IC(50) = 7.5 microM), protein kinase A (IC(50) = 80 microM), and calmodulin-dependent kinase II (IC(50) > 100 microM). NH125 decreased the viability of 10 cancer cell lines with IC(50)s ranging from 0.7 to 4.7 microM. Forced overexpression of eEF-2 kinase in a glioma cell line produced 10-fold resistance to NH125. In conclusion, these results suggest that identification of potent inhibitors of eEF-2 kinase may lead to the development of new types of anticancer drugs.
Arora
Sonia
S
The Cancer Institute of New Jersey, Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
Yang
Jin-Ming
JM
Kinzy
Terri Goss
TG
Utsumi
Ryutaro
R
Okamoto
Tadashi
T
Kitayama
Takashi
T
Ortiz
Pedro A
PA
Hait
William N
WN
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D054736:Elongation Factor 2 Kinase; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C517689:EEF2K protein, human; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054736:Elongation Factor 2 Kinase