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Discovery of Environment-Sensitive Near Infrared SHP2-Targeting Fluorescent Ligands for Living Cells and Tissue
Dong Liang1, Chen Yu2, Yan Lan3
1Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China.
Abstract:
SHP2 protein, a nonreceptor type protein tyrosine phosphatase, is a crucial signal transduction regulator. It interacts with key signaling molecules in the RAS/ERK and PD-1/PD-L1 pathways and significantly affects cell proliferation, differentiation, and immune regulation. It is a promising target for cancer therapy and plays a role in the progression of various tumors. In this study, we report the design and synthesis of near-infrared (NIR) small-molecule fluorescent probes for the recognition and labeling of SHP2. These probes exhibited superior optical properties, strong target affinity, and high selectivity for SHP2. The top-performing probe, SHP-PP2, demonstrated an IC50 of 0.86 μmol/L against SHP2 activity and a Kd of 0.91 μmol/L in binding studies, indicating its potent inhibitory effect and binding affinity. In summary, these probes can effectively enable the visualization of SHP2 in living cells and tissue sections, thereby facilitating further research on SHP2.
Insights
Researchers developed novel near-infrared fluorescent probes to detect SHP2 protein, a key regulator in cancer signaling pathways. The top probe, SHP-PP2, shows high affinity and selectivity, enabling visualization of SHP2 in cells and tissues.
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- SHP2 protein tyrosine phosphatase regulates critical signaling pathways like RAS/ERK and PD-1/PD-L1.
- SHP2 influences cell proliferation, differentiation, and immune responses, making it a significant target in cancer therapy.
- Dysregulation of SHP2 is implicated in the progression of various tumors.
Purpose of the Study:
- To design and synthesize novel near-infrared (NIR) small-molecule fluorescent probes for SHP2 recognition and labeling.
- To evaluate the optical properties, target affinity, and selectivity of these probes for SHP2.
- To demonstrate the utility of these probes for visualizing SHP2 in biological systems.
Main Methods:
- Synthesis of NIR small-molecule fluorescent probes.
- Biochemical assays to determine inhibitory concentration 50 (IC50) against SHP2 activity.
- Binding studies to measure dissociation constant (Kd).
- Cellular and tissue imaging using the developed probes.
Main Results:
- Developed NIR fluorescent probes with superior optical properties.
- The probe SHP-PP2 demonstrated high affinity (Kd = 0.91 μmol/L) and selectivity for SHP2.
- SHP-PP2 exhibited potent inhibition of SHP2 activity (IC50 = 0.86 μmol/L).
- Probes successfully visualized SHP2 in living cells and tissue sections.
Conclusions:
- The developed NIR fluorescent probes are effective tools for SHP2 detection and visualization.
- These probes facilitate research into SHP2's role in cellular processes and disease.
- SHP-PP2 shows promise as a potent inhibitor and imaging agent for SHP2-related research and potential therapeutic applications.
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