title: Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G.
abstract: 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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Moerke
authors.forename: Huseyin
authors.initials: H
authors.lastname: Aktas
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Sonia
authors.initials: S
authors.lastname: Cantel
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Reibarkh
authors.forename: Amr
authors.initials: A
authors.lastname: Fahmy
authors.forename: John D
authors.initials: JD
authors.lastname: Gross
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
mesh_terms: 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*
chemical_list: 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