{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["27(7)"],"submitter":["Sellars E"],"pubmed_abstract":["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."],"journal":["iScience"],"pagination":["110180"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11238136"],"repository":["biostudies-literature"],"pubmed_title":["A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity."],"pmcid":["PMC11238136"],"pubmed_authors":["Narod SA","Salmena L","Savguira M","Wu J","Hakem A","Jen M","Cancelliere S","Hakem R","Kotsopoulos J","Sellars E","Barsyte-Lovejoy D","Krishnan R"],"additional_accession":[]},"is_claimable":false,"name":"A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2025-04-05T15:49:39.951Z","creation":"2025-04-05T15:49:39.951Z"},"accession":"S-EPMC11238136","cross_references":{"pubmed":["38993666"],"doi":["10.1016/j.isci.2024.110180"]}}