Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G.
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.
Moerke
Nathan J
NJ
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Aktas
Huseyin
H
Chen
Han
H
Cantel
Sonia
S
Reibarkh
Mikhail Y
MY
Fahmy
Amr
A
Gross
John D
JD
Degterev
Alexei
A
Yuan
Junying
J
Chorev
Michael
M
Halperin
Jose A
JA
Wagner
Gerhard
G
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D039561:Eukaryotic Initiation Factor-4E / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D016231:Fluorescence Polarization Immunoassay / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006835:Hydrazones; D019169:Jurkat Cells; D051379:Mice; D008958:Models, Molecular; D009574:Nitro Compounds / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D009857:Oncogenes / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013844:Thiazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
C517852:4EGI-1 compound; D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D009574:Nitro Compounds; D010446:Peptide Fragments; D012333:RNA, Messenger; D013844:Thiazoles