biostudies-literatureUnknown27(7)Sellars EPARP inhibitors (PARPi) are efficacious in <i>BRCA1</i>-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in <i>BRCA1</i> wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.iScience110180https://www.ebi.ac.uk/biostudies/studies/S-EPMC11238136biostudies-literatureA high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity.PMC11238136Narod SASalmena LSavguira MWu JHakem AJen MCancelliere SHakem RKotsopoulos JSellars EBarsyte-Lovejoy DKrishnan RfalseA high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity.PARP inhibitors (PARPi) are efficacious in <i>BRCA1</i>-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in <i>BRCA1</i> wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.2024-01-01T00:00:00Z2024 Jul2025-04-05T15:49:39.951Z2025-04-05T15:49:39.951ZS-EPMC112381363899366610.1016/j.isci.2024.110180