Cell-Based Screening for New PARP Inhibitors Utilizing PARG-Mutated Mouse Embryonic Stem Cells.

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.