Frontiers in Bioengineering and Biotechnology (Jun 2022)
Identification of Small-Molecule Inhibitors for Osteosarcoma Targeted Therapy: Synchronizing In Silico, In Vitro, and In Vivo Analyses
Abstract
Objective: The study aimed to explore a new approach for the treatment of osteosarcoma through combining biomaterials with next-generation small molecule–based targeted therapy.Methods: The model of osteosarcoma was established by 4-hydroxyaminoquinoline 1-oxide (4-HAQO) in mice while the collagen-thermosensitive hydrogel–calcium phosphate (CTC) biocomposites were prepared, and the small molecule inhibitors were virtually screened and synthesized. Then, for the osteosarcoma cell line, MG-63 cells were used to validate our bioinformatic findings in vitro, and the mouse osteosarcoma models were treated by combing CTC composites and small-molecule inhibitors after debridement.Results: Five compounds, namely, ZINC150338698, ZINC14768621, ZINC4217203, ZINC169291448, and ZINC85537017, were found in the ZINK database. Finally, ZINC150338698 was selected for chemical synthesis and experimental verification. The results of the MTT assay and Hoechst staining showed that the small-molecule inhibitor ZINC150338698 could significantly induce MG-63 cell death. Furthermore, CTC composites and ZINC150338698 could repair the bone defects well after the debridement of osteosarcoma. In addition, the biomaterials and small-molecule inhibitors have good biocompatibility and biosafety.Conclusion: Our findings not only offer systems biology approach-based drug target identification but also provide new clues for developing novel treatment methods for future osteosarcoma research.
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