1. Academic Validation
  2. Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors

Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors

  • Eur J Med Chem. 2014 Apr 22;77:361-77. doi: 10.1016/j.ejmech.2014.03.034.
Khuloud Takrouri 1 Ting Chen 1 Evangelos Papadopoulos 2 Rupam Sahoo 1 Eihab Kabha 3 Han Chen 3 Sonia Cantel 3 Gerhard Wagner 2 Jose A Halperin 1 Bertal H Aktas 1 Michael Chorev 4
Affiliations

Affiliations

  • 1 Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
  • 3 Laboratory for Translational Research, Harvard Medical School, USA.
  • 4 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.
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.

Keywords

4EGI-1; E/Z-isomerization; Florescence polarization assay; Hydrazones; Inhibitors of protein–protein interaction; Thiazol-2-yl hydrazones; Translation initiation; eIF4F.

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