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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.
Abstract:
According to the most recent data, cancer is among the leading cause of death in the United States and accounted for more than 600,000 deaths in 2021. Around 30% of these cancer-related deaths were caused by breast, prostate, and ovarian cancers. PARP-1 inhibitors show the most promising results in treatment of these three types of cancers and have found widespread use in the development of novel treatment strategies. A number of PARP inhibitors currently are undergoing phase I/II of FDA approval process for treatment of genetically disposed mutant tumors. Recently, however, a few clinical studies reported setbacks in research on PARP-1 inhibitors. It is likely that these setbacks are caused by tremendous off-target effects. To overcome these problems, it is very important to design new potent PARP-1 inhibitors, which do not kill normal cells. Our newly developed assay is based on the usage of sensitized embryonic stem cells with disrupted PARG gene that significantly increase the base level of pADPr for easy detection. Our approach allows the discovery of that effectively target poly(ADP-ribosyl)ation in cells and allows to select compounds with minimal or no cytotoxic effects on ES cells.
Insights
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.
