2. Academic Validation
  3. Identification of EEF1A2 as a potential therapy target of osteosarcoma using novel compound 8e

Identification of EEF1A2 as a potential therapy target of osteosarcoma using novel compound 8e

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118355. doi: 10.1016/j.ejmech.2025.118355.
Jian Xue 1,  Meng Li 2,  Ying Wang 1,  Donghui Sun 1,  Shilong Hao 1,  Zhuochao Liu 3,  Weibin Zhang 3,  Lei Li 4,  Tong Zhu 1,  Shunying Liu 5
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China; Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3 Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200062, China.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
PMID: 41252934 DOI: 10.1016/j.ejmech.2025.118355
Abstract

Osteosarcoma (OS) is a rare malignant tumor and has the second-highest mortality rate of malignant tumors in children. Due to its unclear pathogenesis and therapeutic targets, there has been no significant progress in the targeted therapy of OS in the past 50 years. Therefore, it is critically important to develop new drug targets for OS. In this study, a covalent molecule library consisting of 61 small molecules was constructed based on our previous research. Phenotypic screening revealed that small molecule 8e effectively inhibited the proliferation of OS 143B cells, with an IC50 value of 0.73 μM. Compound 8e also showed good antitumor effects and low toxicity in a xenograft model (30.1 % inhibition of OS growth in BALB/c nude mice). Using compound 9a as an efficient activity-based protein profiling (ABPP) probe, eukaryotic protein elongation factor 1 alpha 2 (EEF1A2) was then enriched and conveniently identified as a potential target. The potential target was validated by pull-down assay, cellular thermal shift assay (CETSA), mass spectrometry analysis, molecular docking, and in vitro and in vivo functional studies. Mechanistic studies suggest that compound 8e-induced 143B cell apoptotic is mediated by EEF1A2 inhibition of the Akt signaling pathway and EEF1A2 serves as a potential candidate for targeted OS therapy.

Keywords

ABPP; Covalent molecule library; EEF1A2; Osteosarcoma; Target identification.

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