{"doi":"10.1038/s41598-024-70858-w","title":"Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441","abstract":"DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a vital role in DNA damage repair and lymphocyte function, presenting a significant target in cancer and immune diseases. Current DNA-PKcs inhibitors are undergoing Phase I/II trials as adjuncts to radiotherapy and chemotherapy in cancer. Nevertheless, clinical utility is limited by suboptimal bioavailability. This study introduces DNA-PKcs inhibitors designed to enhance bioavailability. We demonstrate that a novel DNA-PKcs inhibitor, DA-143, surpasses NU7441 in aqueous solubility as well as other available inhibitors. In addition, DA-143 displayed an improvement in DNA-PKcs inhibition relative to NU7441 achieving an IC 50 of 2.5 nM. Consistent with current inhibitors, inhibition of DNA-PKcs by DA-143 resulted in increased tumor cell sensitivity to DNA-damage from chemotherapy and inhibition of human T cell function. The improved solubility of DA-143 is critical for enhanced efficacy at reduced doses and facilitates more effective evaluation of DNA-PKcs inhibition in both preclinical and clinical development.","journal":"Scientific Reports","year":2024,"id":468971,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9647,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1074956,"name":"Baku Acharya","orcid":"0009-0005-6511-8645","position":1,"is_corresponding":false},{"id":291584,"name":"Daniel W. Armstrong","orcid":"0000-0003-0501-6231","position":2,"is_corresponding":false},{"id":1075535,"name":"Maha Hanafi","orcid":null,"position":3,"is_corresponding":false},{"id":1130737,"name":"Randall R Rainwater","orcid":"0009-0002-0840-1784","position":4,"is_corresponding":false},{"id":1302787,"name":"Sharon Amole","orcid":null,"position":5,"is_corresponding":false},{"id":1302788,"name":"Madeline Fulmer","orcid":null,"position":6,"is_corresponding":false},{"id":532240,"name":"Ana Clara P. Azevedo‐Pouly","orcid":"0000-0001-8308-9271","position":7,"is_corresponding":false},{"id":1302408,"name":"Alaina Burns","orcid":"0000-0003-4261-6076","position":8,"is_corresponding":false},{"id":719527,"name":"Lyle Burdine","orcid":"0000-0002-5892-2281","position":9,"is_corresponding":false},{"id":488294,"name":"Brendan Frett","orcid":"0000-0003-2429-8895","position":10,"is_corresponding":false},{"id":720112,"name":"Marie Burdine","orcid":null,"position":11,"is_corresponding":false},{"id":719526,"name":"Zachary J. Waldrip","orcid":"0000-0002-4210-8832","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:05:28.027781Z","pmid":"39198533","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":[]}