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Identification of Nogo-B as a potential therapeutic target of osteosarcoma via stereochemically selective covalent
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) has been defined as one of the most intricate and formidable malignant bone tumors, and there has been no significant improvement in targeted therapies for OS over the past 50 years. Therefore, it is crucial to identify new potential drug targets for OS. Here, we have developed a label-free activity-based protein profiling (ABPP) using a stereochemically selective probe from an in-house patrimonial library of covalent small molecule compounds to identify an anti-OS target. Phenotypic screening resulted in the discovery of a selective inhibitor (S,R)-4v that potently suppresses the proliferation of OS 143B cells with an IC50 value of 0.28 µM. Subsequent label-free ABPP studies identified neurite outgrowth inhibitor B (Nogo-B) as the primary cellular target for (S,R)-4v via a rapid relatively quantitative analysis using its inactive isomer as control. This finding was validated by interaction assays including pull-down, cellular thermal shift assay (CETSA), molecular docking and functional studies. Mechanistic investigations revealed that the apoptotic effect induced by (S,R)-4v was mediated through Nogo-B inhibition of the PI3K/AKT-dependent NF-κB pathway. Altogether, this study presents a novel strategy that couples anti-OS compound screening with target identification and successfully identifies Nogo-B as a potential candidate for targeted OS therapy.
Insights
Researchers identified Nogo-B as a potential drug target for osteosarcoma (OS). A novel compound, (S,R)-4v, selectively inhibits Nogo-B, suppressing OS cell proliferation and inducing apoptosis via the PI3K/AKT/NF-κB pathway.
Area of Science:
- Oncology
- Biochemistry
- Drug Discovery
Background:
- Osteosarcoma (OS) is a challenging bone tumor with limited therapeutic advancements.
- Identifying novel drug targets is critical for effective OS treatment.
Purpose of the Study:
- To identify a new therapeutic target for osteosarcoma.
- To develop a novel compound and screening strategy for OS drug discovery.
Main Methods:
- Developed a label-free activity-based protein profiling (ABPP) assay.
- Screened a library of covalent small molecules to identify OS inhibitors.
- Used phenotypic screening and ABPP to identify the cellular target of a novel inhibitor.
Main Results:
- Discovered (S,R)-4v, a selective inhibitor of OS 143B cell proliferation (IC50=0.28 µM).
- Identified Nogo-B as the primary cellular target of (S,R)-4v using ABPP.
- Validated Nogo-B as the target through pull-down, CETSA, molecular docking, and functional assays.
- Demonstrated that (S,R)-4v induces apoptosis by inhibiting Nogo-B, which affects the PI3K/AKT/NF-κB pathway.
Conclusions:
- Nogo-B is a potential therapeutic target for osteosarcoma.
- (S,R)-4v is a promising lead compound for osteosarcoma therapy.
- This study presents a novel strategy for coupling compound screening with target identification in OS.
