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Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening
Amit Subedi1, Takeshi Shimizu2, Akihide Ryo3
1Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, Saitama, 338-8570, Japan.
Abstract:
Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation.
Insights
Researchers developed a new screening system to find Pin1 inhibitors, crucial for cancer therapy. This led to the discovery of novel selenium-based compounds that effectively inhibit cancer cell growth.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Pin1 (Peptidyl prolyl cis/trans isomerase) regulates oncogenic signals critical for cancer progression.
- Pin1 is a validated therapeutic target, but limited screening systems hinder inhibitor discovery.
Purpose of the Study:
- To develop a simplified screening system for identifying Pin1 inhibitors.
- To discover novel Pin1 inhibitors for potential cancer therapy.
Main Methods:
- Developed a screening system based on Pin1's phosphorylation-dependent substrate binding.
- Screened a chemical library using the developed system.
- Identified a novel selenium derivative as a Pin1 inhibitor.
- Performed structure-activity guided synthesis to optimize inhibitor potency.
Main Results:
- Successfully established a novel screening system for Pin1 inhibitors.
- Identified a novel selenium derivative with Pin1 inhibitory activity.
- Synthesized more potent Pin1 inhibitors through structure-activity relationship studies.
- Demonstrated that the developed inhibitors suppressed cancer cell proliferation.
Conclusions:
- The developed screening system is effective for discovering Pin1 inhibitors.
- Novel selenium derivatives show promise as potent Pin1 inhibitors.
- Targeting Pin1 with these novel inhibitors could offer a new therapeutic strategy for cancer treatment.
