{"doi":"10.1016/j.jbc.2025.108361","title":"Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells","abstract":null,"journal":"Journal of Biological Chemistry","year":2025,"id":612732,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1577795,"name":"Seher Alam","orcid":"0000-0002-8494-832X","position":1,"is_corresponding":false},{"id":648208,"name":"Alen Lovrić","orcid":"0000-0001-5778-9928","position":2,"is_corresponding":false},{"id":1577798,"name":"Emanuele Fabbrizi","orcid":null,"position":3,"is_corresponding":false},{"id":295618,"name":"Dante Rotili","orcid":"0000-0002-8428-8763","position":4,"is_corresponding":false},{"id":750755,"name":"Mikael Altun","orcid":"0000-0002-6937-6124","position":5,"is_corresponding":false},{"id":1184036,"name":"Nicholas C.K. Valerie","orcid":"0000-0002-9423-964X","position":6,"is_corresponding":false},{"id":1577793,"name":"Maria J. Pires","orcid":"0009-0007-0384-091X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells","abstract":"Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) targeting PARP1 and PARP2 have revolutionized cancer therapy by selectively killing cancer cells with defective DNA repair. However, achieving PARP1 or PARP2-selective inhibitors is difficult due to structural homology. Selectivity profiling is typically done with purified proteins, but these lack the complexity of intracellular environments and could therefore be inaccurate. Here, we duplex PARP1 L713F-GFP and PARP2 L269A-mCherry cellular target engagement by accumulation of mutant (CeTEAM) drug biosensors to systematically characterize binding and cell cycle alterations of 27 PARPi. Our results reveal that most PARPi are equipotent for both PARPs, including the next-generation drug, senaparib. However, benzimidazole carboxamide (niraparib) derivatives demonstrated PARP1-selective tendencies, while phthalazinones (olaparib) favored PARP2. AZD5305, a reported PARP1-selective inhibitor with characteristics of both series, was the exception and appears ∼1600-fold more potent toward PARP1. In agreement with current understanding, we see that trapping-associated S/G2-phase transitions positively correlate with PARP1/2 binding potency, while some potent binders, such as veliparib, did not - likely reflecting their allosteric influence on DNA retention. We also assessed the effect of the PARP1/2 active site component, histone PARylation factor 1, on intracellular PARPi binding and see that its depletion elicits slight deviations in apparent binding potency, while contributing additively to trapping-like phenotypes. The PARP1/2 CeTEAM platform thus provides a structural roadmap for the development of selective PARPi and should facilitate the discovery of targeted therapies. Furthermore, our results highlight that multiplexing CeTEAM biosensors and layered genetic perturbations can systematically profile determinants of intracellular drug selectivity.","is_dataset_classified":null,"base_score":1.791759469228055,"endowment":1.791759469228055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40021124","pmcid":"PMC11986510","openalex_id":"https://openalex.org/W4407958519","authors":[],"funders":[{"funder_name":"Novo Nordisk Foundation","grant_id":"NNF22OC0076798","title":null},{"funder_name":"Horizon 2020 Marie Skłodowska-Curie Actions","grant_id":"859860","title":"Innovative strategies for cancer prevention with focus on sex hormone signaling and chronic inflammation"},{"funder_name":"Ministero dell’Istruzione, dell’Università e della Ricerca","grant_id":"PNRR-M4C2","title":null},{"funder_name":"Ministero dell’Istruzione, dell’Università e della Ricerca","grant_id":"CUP B53C22004000006","title":null},{"funder_name":"Ministero dell’Istruzione, dell’Università e della Ricerca","grant_id":"PE_00000019","title":null},{"funder_name":"Childhood Cancer Foundation","grant_id":"TJ2019\\u20130036","title":null},{"funder_name":"Loo and Hans Osterman Foundation for Medical Research","grant_id":"2020-01208","title":null},{"funder_name":"Cancerfonden","grant_id":"21 0352 PT \\u2013 NV","title":null},{"funder_name":"Cancerfonden","grant_id":"21 0352 PT","title":null},{"funder_name":"Ministero dell'Istruzione dell'Università e della Ricerca","grant_id":"unidentified","title":"unidentified"},{"funder_name":"SciLifeLab","grant_id":"","title":null},{"funder_name":"Bertil Hållsten's Research Foundation","grant_id":"","title":null},{"funder_name":"European Commission","grant_id":"","title":null},{"funder_name":"Novo Nordisk","grant_id":"","title":null},{"funder_name":"Ministero dell'Università e della Ricerca","grant_id":"","title":null},{"funder_name":"Horizon 2020","grant_id":"","title":null},{"funder_name":"Karolinska Institutet","grant_id":"","title":null},{"funder_name":"Felix Mindus Foundation's contribution to leukemia research","grant_id":"","title":null},{"funder_name":"Horizon 2020 Framework Programme","grant_id":"","title":null}],"total_grants":19,"fwci":2.4551,"citation_percentile":0.89336312,"influential_citations":0,"citation_trend":[{"year":2025,"count":4},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.jbc.org/article/S0021-9258(25)00210-8/pdf","host_type":"journal"},{"url":"https://www.jbc.org/article/S0021-9258(25)00210-8/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925825002108?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925825002108?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.jbc.2025.108361","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40021124","host_type":"repository"},{"url":"https://hdl.handle.net/11590/518928","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11986510","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11986510","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11986510?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1016/j.jbc.2025.108361","host_type":""},{"url":"https://publications.scilifelab.se/publication/8f813a953a47489dbce089b11fc24f50","host_type":""}],"fields_of_study":["PARP inhibition in cancer therapy","Integrated Circuits and Semiconductor Failure Analysis","Ion-surface interactions and analysis","Humans","Poly(ADP-ribose) Polymerase Inhibitors","Biosensing Techniques","Poly (ADP-Ribose) Polymerase-1","Poly(ADP-ribose) Polymerases","Phthalazines","Piperazines"],"mesh_terms":["Poly(ADP-ribose) Polymerase Inhibitors","Poly (ADP-Ribose) Polymerase-1","Humans","Phthalazines","Piperazines","Poly(ADP-ribose) Polymerases","Biosensing Techniques"],"keywords":["Biosensor","Drug","PARP inhibitor","Selectivity","Chemistry","Computational biology","Poly ADP ribose polymerase","Drug discovery","Pharmacology","Combinatorial chemistry","Biology","Biochemistry","Gene","Protein engineering","Fluorescence","Parp Inhibitors","Drug Selectivity","Hpf1","Cellular Target Engagement","Ceteam","Poly (ADP-Ribose) Polymerase-1","Humans","Phthalazines","Biosensing Techniques","CeTEAM; HPF1; PARP inhibitors; biosensor; cellular target engagement; drug discovery; drug selectivity; fluorescence; pharmacology; protein engineering","Poly(ADP-ribose) Polymerase Inhibitors","Poly(ADP-ribose) Polymerases","Piperazines","Research Article"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Zero hunger"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T04:43:32.629633Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}