Descubrimiento de un inhibidor de molécula pequeña de eIF4E que suprime la proliferación tumoral mediante la...

The eukaryotic translation initiation factor 4E (eIF4E) has emerged as a compelling target for cancer therapeutics due to its pivotal role in regulating cap-dependent translation of oncogenic mRNAs and its implication in various malignancies. However, the clinical potential of current eIF4E inhibitors is limited by suboptimal potency and binding affinity.

Based on an analysis of the eIF4E/eIF4G binding pocket and structural features of existing inhibitors, 75 compounds were designed, synthesized, and screened. The binding affinity, molecular mechanism and antitumor activity of the most potent compound b14 were evaluated in vitro and in vivo.

Through structure-activity relationship analysis, 75 thiazole derivatives were synthesized and screened for binding affinity using fluorescence polarization (FP) and surface plasmon resonance (SPR). Hit compounds were evaluated for antitumor activity using the SRB assay. The most promising compound, b14, was further investigated for its antitumor activity and molecular mechanism via Western blotting (WB), quantitative real-time PCR (qRT-PCR), immunofluorescence, co-immunoprecipitation, and proteomics. The in vivo antitumor activity and safety of b14 were assessed using HeLa xenograft models and acute/subacute toxicity models, respectively.

Compound b14 emerged as a lead molecule, exhibiting a 10-fold higher binding affinity to eIF4E than the reference inhibitor 4EGI-1. Mechanistic studies revealed that b14 disrupts eIF4F complex formation by inhibiting AKT-mTOR-4EBP1 and ERK-eIF4E phosphorylation, subsequently triggering mitochondrial dysfunction and apoptosis in tumor cells, with relatively low IC₅₀ values. Moreover, proteomics analysis further demonstrated that b14 suppresses oncogenic lipogenesis by downregulating key enzymes involved in lipid metabolism. Finally, oral administration of b14 significantly inhibits HeLa xenograft growth in vivo without measurable side effects.

Together, our results demonstrate that b14 is an excellent novel small-molecule inhibitor of eIF4E for future cancer therapy.