TY - JOUR
T1 - Small-Molecule Inhibition of the Interaction between the Translation Initiation Factors eIF4E and eIF4G
AU - Moerke, Nathan J.
AU - Aktas, Huseyin
AU - Chen, Han
AU - Cantel, Sonia
AU - Reibarkh, Mikhail Y.
AU - Fahmy, Amr
AU - Gross, John D D.
AU - Degterev, Alexei
AU - Yuan, Junying
AU - Chorev, Michael
AU - Halperin, Jose A.
AU - Wagner, Gerhard
PY - 2007/1/26
Y1 - 2007/1/26
N2 - Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation. This complex is regulated by the 4E-BPs, which compete with eIF4G for binding to eIF4E and which have tumor-suppressor activity. To pharmacologically mimic 4E-BP function we developed a high-throughput screening assay for identifying small-molecule inhibitors of the eIF4E/eIF4G interaction. The most potent compound identified, 4EGI-1, binds eIF4E, disrupts eIF4E/eIF4G association, and inhibits cap-dependent translation but not initiation factor-independent translation. While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells. 4EGI-1 inhibits cellular expression of oncogenic proteins encoded by weak mRNAs, exhibits activity against multiple cancer cell lines, and appears to have a preferential effect on transformed versus nontransformed cells. The identification of this compound provides a new tool for studying translational control and establishes a possible new strategy for cancer therapy.
AB - Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation. This complex is regulated by the 4E-BPs, which compete with eIF4G for binding to eIF4E and which have tumor-suppressor activity. To pharmacologically mimic 4E-BP function we developed a high-throughput screening assay for identifying small-molecule inhibitors of the eIF4E/eIF4G interaction. The most potent compound identified, 4EGI-1, binds eIF4E, disrupts eIF4E/eIF4G association, and inhibits cap-dependent translation but not initiation factor-independent translation. While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells. 4EGI-1 inhibits cellular expression of oncogenic proteins encoded by weak mRNAs, exhibits activity against multiple cancer cell lines, and appears to have a preferential effect on transformed versus nontransformed cells. The identification of this compound provides a new tool for studying translational control and establishes a possible new strategy for cancer therapy.
UR - https://www.scopus.com/pages/publications/33846449110
U2 - 10.1016/j.cell.2006.11.046
DO - 10.1016/j.cell.2006.11.046
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C2 - 17254965
AN - SCOPUS:33846449110
SN - 0092-8674
VL - 128
SP - 257
EP - 267
JO - Cell
JF - Cell
IS - 2
ER -
