Probe Synthesis Reveals Eukaryotic Translation Elongation Factor 1 Alpha 1 as the Anti-Pancreatic Cancer Target of BE-43547A₂

The natural product, BE-43547A₂, decreases pancreatic cancer cell stemness. However, its anticancer molecular mechanisms have not been fully established. Based on structure–activity relationships of BE-43547A₂, we synthesized a probe and investigated its potential targets using an in situ click reaction. We found that BE-43547A₂ exerts its anticancer effects by covalently binding the cysteine234 (C234) residue of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). This binding mode was confirmed by a series of experiments including a xenograft mouse model. We also determined that eEF1A1 plays an important role in regulating pancreatic cancer cell stemness. Analyses of 99 clinical pancreatic cancer samples revealed that eEF1A1 expressions are closely correlated with clinicopathological grade and patient survival. In conclusion, eEF1A1 is involved in pancreatic cancer progression and is therefore, a promising novel covalent target for pancreatic cancer treatment.