3‐Substituted Indazoles as Configurationally Locked 4EGI‐1 Mimetics and Inhibitors of the eIF4E/eIF4G Interaction

• DOI: 10.1002/cbic.201300723
• Publication Date: 2014-01-23T17:49:00Z
• Authors: Revital Yefidoff‐...; Ting Chen; Rupam Sahoo; Limo Chen; Gerhard Wagner; Jose A. Halperin; Bertal H. Aktas; Michael Chorev
• Keywords: 0303 health sciences; Indazoles; Hydrazones; Stereoisomerism; Structure-Activity Relationship; Thiazoles; 03 medical and health sciences; Eukaryotic Initiation Factor-4E; Cell Line, Tumor; Humans; Protein Interaction Domains and Motifs; Eukaryotic Initiation Factor-4G; Cell Proliferation; Protein Binding

Abstract4EGI‐1, the prototypic inhibitor of eIF4E/eIF4G interaction, was identified in a high‐throughput screening of small‐molecule libraries with the aid of a fluorescence polarization assay that measures inhibition of binding of an eIF4G‐derived peptide to recombinant eIF4E. As such, the molecular probe 4EGI‐1 has potential for the study of molecular mechanisms involved in human disorders characterized by loss of physiological restraints on translation initiation. A hit‐to‐lead optimization campaign was carried out to overcome the configurational instability in 4EGI‐1, which stems from the E‐to‐Z isomerization of the hydrazone function. We identified compound 1 a, in which the labile hydrazone was incorporated into a rigid indazole scaffold, as a promising rigidified 4EGI‐1 mimetic lead. In a structure–activity relationship study directed towards probing the structural latitude of this new chemotype as an inhibitor of eIF4E/eIF4G interaction and translation initiation we identified 1 d, an indazole‐based 4EGI‐1 mimetic, as a new and improved lead inhibitor of eIF4E/eIF4G interaction and a promising molecular probe candidate for elucidation of the role of cap‐dependent translation initiation in a host of pathophysiological states.