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

Angew Chem Int Ed Engl. 2022 Aug 22;61(34):e202206953. doi: 10.1002/anie.202206953. Epub 2022 Jul 11.

Abstract

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.

Keywords: Anticancer Target; BE-43547; Pancreatic Cancer; Target Identification; eEF1A.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Biological Products / therapeutic use
  • Click Chemistry
  • Humans
  • Mice
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Peptide Elongation Factor 1* / chemistry
  • Peptide Elongation Factor 1* / genetics
  • Peptide Elongation Factor 1* / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biological Products
  • EEF1A1 protein, human
  • Eef1a1 protein, mouse
  • Peptide Elongation Factor 1