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Published on: May 3, 2021
Identification of EEF1A2 as a potential therapy target of osteosarcoma using novel compound 8e
Jian Xue1, Meng Li2, Ying Wang1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
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.
Insights
Researchers identified a new potential drug target, eukaryotic elongation factor 1 alpha 2 (EEF1A2), for osteosarcoma (OS). A novel small molecule, 8e, effectively inhibited OS cell proliferation and tumor growth by targeting EEF1A2.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Osteosarcoma (OS) is a rare pediatric cancer with high mortality and limited therapeutic advancements.
- The lack of clear pathogenesis and therapeutic targets has hindered progress in OS treatment for decades.
- Developing novel drug targets is crucial for improving OS therapy.
Purpose of the Study:
- To identify novel therapeutic targets for osteosarcoma (OS).
- To evaluate the efficacy of a newly synthesized small molecule (8e) against OS.
- To elucidate the mechanism of action and validate the identified target.
Main Methods:
- Construction of a covalent small molecule library and phenotypic screening.
- Activity-based protein profiling (ABPP) using compound 9a to identify protein targets.
- Validation of the target using pull-down assays, CETSA, mass spectrometry, and molecular docking.
- In vitro and in vivo functional studies in OS cells and xenograft models.
Main Results:
- Small molecule 8e demonstrated potent inhibition of OS 143B cell proliferation (IC50 = 0.73 μM).
- Compound 8e exhibited significant antitumor effects (30.1% inhibition) with low toxicity in a xenograft model.
- Eukaryotic elongation factor 1 alpha 2 (EEF1A2) was identified as a potential target of compound 8e.
- EEF1A2 inhibition by 8e suppressed the AKT signaling pathway, leading to OS cell apoptosis.
Conclusions:
- EEF1A2 is a promising therapeutic target for osteosarcoma.
- Small molecule 8e shows potential as a novel therapeutic agent for OS by inhibiting EEF1A2.
- Targeting EEF1A2 offers a new strategy for developing effective osteosarcoma therapies.
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