title: Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors.
abstract: Protein-protein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2-nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G protein-protein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities.
authors.affiliation: Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
authors.forename: Khuloud
authors.initials: K
authors.lastname: Takrouri
authors.affiliation: Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadopoulos
authors.affiliation: Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
authors.forename: Rupam
authors.initials: R
authors.lastname: Sahoo
authors.affiliation: Laboratory for Translational Research, Harvard Medical School, USA.
authors.forename: Eihab
authors.initials: E
authors.lastname: Kabha
authors.affiliation: Laboratory for Translational Research, Harvard Medical School, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Laboratory for Translational Research, Harvard Medical School, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cantel
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.affiliation: Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
authors.affiliation: Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
authors.affiliation: Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA. Electronic address: michael_chorev@hms.harvard.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D029543:Nucleocytoplasmic Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C517852:4EGI-1 compound; C411571:EIF4ENIF1 protein, human; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D029543:Nucleocytoplasmic Transport Proteins; D013844:Thiazoles
keywords: 4EGI-1; E/Z-isomerization; Florescence polarization assay; Hydrazones; Inhibitors of protein–protein interaction; Thiazol-2-yl hydrazones; Translation initiation; eIF4F