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Cell-Based Screening for New PARP Inhibitors Utilizing PARG-Mutated Mouse Embryonic Stem Cells
Yaroslava Karpova1,2, Danping Guo1, Alexei V Tulin3
1Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA.
Methods in Molecular Biology (Clifton, N.J.)
|December 14, 2022
Summary
Developing new cancer drugs like poly(ADP-ribosyl)ation inhibitors requires careful testing. Our new assay uses stem cells to find effective PARP-1 inhibitors with fewer side effects.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Drug Discovery and Development
Background:
- Cancer remains a leading cause of death, with breast, prostate, and ovarian cancers contributing significantly to mortality.
- Poly(ADP-ribosyl)ation (PARP-1) inhibitors are promising for treating these cancers but face challenges due to off-target effects.
- Existing PARP-1 inhibitor research has encountered setbacks, necessitating the development of more targeted and safer therapeutic agents.
Purpose of the Study:
- To develop a novel assay for identifying potent PARP-1 inhibitors.
- To discover compounds that effectively target poly(ADP-ribosyl)ation with minimal cytotoxic effects on normal cells.
- To overcome the limitations of current PARP-1 inhibitors by reducing off-target toxicity.
Main Methods:
- Utilized sensitized embryonic stem cells with a disrupted PARG gene.
- Enhanced the base level of pADPr for improved detection sensitivity.
- Screened compounds to identify effective poly(ADP-ribosyl)ation inhibitors with low cytotoxicity.
Main Results:
- The developed assay successfully increased the detection of poly(ADP-ribosyl)ation.
- Identified compounds that effectively target poly(ADP-ribosyl)ation pathways.
- Selected compounds demonstrating minimal or no cytotoxic effects on embryonic stem cells.
Conclusions:
- The novel assay provides a sensitive platform for discovering PARP-1 inhibitors.
- This approach facilitates the selection of drug candidates with improved safety profiles.
- The findings pave the way for developing next-generation PARP-1 inhibitors for cancer therapy.
