3-substituted indazoles as configurationally locked 4EGI-1 mimetics and inhibitors of the eIF4E/eIF4G interaction.
4EGI-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.
Laboratory for Translational Research, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115 (USA); Hematology Laboratory for Translational Research, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115 (USA).
Revital
R
Yefidoff-Freedman
Ting
T
Chen
Rupam
R
Sahoo
Limo
L
Chen
Gerhard
G
Wagner
Jose A
JA
Halperin
Bertal H
BH
Aktas
Michael
M
Chorev
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
C517852:4EGI-1 compound; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D007191:Indazoles; D013844:Thiazoles
eIF4E/eIF4G interaction; inhibitors; molecular probes; protein-protein interactions; translation initiation