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Achieving dual-target fluorescent probes for tracing and inhibiting BRD4/PLK1 in tumor cells and tissues
Yuqi Gao1, Jianjun Li2, Zhen Ye3
1Department of Medicinal Chemistry, School of Pharmacy, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University, Jinan, Shandong, 250117, China; School of Radiology, Shandong First Medical University, Taian, Shandong, 271016, China.
Abstract:
The concept of kinase-bromodomain dual targeted cancer therapeutics arose in recent years. Thus, the synergistic effects of the combination inhibition of bromodomain-containing protein 4 (BRD4) and polo-like kinase 1 (PLK1) attracted the researchers' attention for the great potential for cancer treatment. In this work, we designed and synthesized a series of small-molecule fluorescent probes targeting BRD4 and PLK1 based on our previous achievements on the study of BRD4 probes, aiming to construct a theragnostic system for cells and tissues. Among the probes, L1 exhibited a good binding affinity toward both PLK1 and BRD4 proteins, and its performances on target protein tracing in both cells and tissues as well were also impressive. By inhibiting PLK1 and BRD4, L1 took on obvious tumor cell suppressive activity that was similar to its pharmacophore BI-2536. Furthermore, the mechanism study revealed that dual inhibition of BRD4 and PLK1 modulated the key genes involving the cell cycle and apoptosis pathways, overcoming compensatory effects compared with the single-target inhibitors. Our work would provide a reliable toolkit for the development of PLK1/BRD4 dual-target inhibitors for cancer diagnostic and therapeutic agents, and bring out the ideas and cases for the design of visualization and therapy dual functional probes.
Insights
Researchers developed a novel fluorescent probe, L1, for dual targeting of bromodomain-containing protein 4 (BRD4) and polo-like kinase 1 (PLK1). This probe shows promise for cancer theranostics by visualizing and inhibiting key cancer-related proteins.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Kinase-bromodomain dual-targeted cancer therapeutics are an emerging field.
- Inhibiting bromodomain-containing protein 4 (BRD4) and polo-like kinase 1 (PLK1) offers synergistic potential for cancer treatment.
Purpose of the Study:
- To design and synthesize small-molecule fluorescent probes targeting both BRD4 and PLK1.
- To develop a theragnostic system for simultaneous diagnosis and therapy of cancer cells and tissues.
Main Methods:
- Synthesis of novel small-molecule fluorescent probes based on previous BRD4 probe research.
- Evaluation of probe binding affinity to PLK1 and BRD4 proteins.
- Assessment of probe performance in target protein tracing in cells and tissues.
- Investigation of the mechanism of action, including effects on cell cycle and apoptosis pathways.
Main Results:
- Probe L1 demonstrated significant binding affinity for both PLK1 and BRD4.
- L1 showed impressive performance in tracing target proteins in cellular and tissue models.
- L1 exhibited notable tumor cell suppressive activity, comparable to existing pharmacophores.
- Dual inhibition of BRD4 and PLK1 by L1 modulated key genes in cell cycle and apoptosis, overcoming single-target inhibitor limitations.
Conclusions:
- The developed fluorescent probe L1 serves as a reliable tool for PLK1/BRD4 dual-target inhibitor development.
- This work provides a foundation for creating dual-functional probes for cancer visualization and therapy.
- The findings support the advancement of theranostic agents for improved cancer treatment strategies.
