{"doi":"10.1073/pnas.1200037109","title":"Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1–CBFβ interaction","abstract":"<jats:p>\n                    Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes\n                    <jats:italic>RUNX1</jats:italic>\n                    or\n                    <jats:italic>CBFB</jats:italic>\n                    , account for ∼24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of ∼50%. We hypothesize that the interaction between RUNX1 and CBFβ is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1–CBFβ interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBFβ directly, repress\n                    <jats:italic>RUNX1/CBFB</jats:italic>\n                    -dependent transactivation in reporter assays, and repress\n                    <jats:italic>runx1</jats:italic>\n                    -dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a\n                    <jats:italic>RUNX1–ETO</jats:italic>\n                    transgenic zebrafish, and reduced leukemia burden in a mouse\n                    <jats:italic>CBFB–MYH11</jats:italic>\n                    leukemia model. Our data thus confirmed that RUNX1–CBFβ interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2012,"id":598667,"datarank":0.7379971388742189,"base_score":4.919980925828125,"endowment":4.919980925828125,"self_citation_contribution":0.7379971388742189,"citation_network_contribution":0.0,"self_endowment_contribution":0.7379971388742189,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":136,"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":1534260,"name":"Steven Finckbeiner","orcid":null,"position":1,"is_corresponding":false},{"id":503528,"name":"R. Katherine Hyde","orcid":"0000-0003-2808-1749","position":2,"is_corresponding":false},{"id":95324,"name":"Noel Southall","orcid":"0000-0003-4500-880X","position":3,"is_corresponding":false},{"id":505883,"name":"Juan Marugan","orcid":null,"position":4,"is_corresponding":false},{"id":790314,"name":"Venkat R. K. Yedavalli","orcid":null,"position":5,"is_corresponding":false},{"id":1534261,"name":"Seameen Jean Dehdashti","orcid":null,"position":6,"is_corresponding":false},{"id":241967,"name":"William C. Reinhold","orcid":"0000-0001-5513-9323","position":7,"is_corresponding":false},{"id":478412,"name":"Lemlem Alemu","orcid":null,"position":8,"is_corresponding":false},{"id":395307,"name":"Ling Zhao","orcid":"0000-0002-0811-3160","position":9,"is_corresponding":false},{"id":599783,"name":"Jing-Ruey Joanna Yeh","orcid":"0000-0002-7768-4901","position":10,"is_corresponding":false},{"id":147058,"name":"Raman Sood","orcid":null,"position":11,"is_corresponding":false},{"id":185421,"name":"Yves Pommier","orcid":null,"position":12,"is_corresponding":false},{"id":110635,"name":"Christopher P. Austin","orcid":null,"position":13,"is_corresponding":false},{"id":1505395,"name":"Kuan-Teh Jeang","orcid":null,"position":14,"is_corresponding":false},{"id":790966,"name":"Wei Zheng","orcid":"0000-0003-0021-6672","position":15,"is_corresponding":false},{"id":232072,"name":"Paul Liu","orcid":"0000-0002-6779-025X","position":16,"is_corresponding":false},{"id":886350,"name":"Lea Cunningham","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1–CBFβ interaction","abstract":"<jats:p>\n                    Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes\n                    <jats:italic>RUNX1</jats:italic>\n                    or\n                    <jats:italic>CBFB</jats:italic>\n                    , account for ∼24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of ∼50%. We hypothesize that the interaction between RUNX1 and CBFβ is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1–CBFβ interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBFβ directly, repress\n                    <jats:italic>RUNX1/CBFB</jats:italic>\n                    -dependent transactivation in reporter assays, and repress\n                    <jats:italic>runx1</jats:italic>\n                    -dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a\n                    <jats:italic>RUNX1–ETO</jats:italic>\n                    transgenic zebrafish, and reduced leukemia burden in a mouse\n                    <jats:italic>CBFB–MYH11</jats:italic>\n                    leukemia model. Our data thus confirmed that RUNX1–CBFβ interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose.\n                  </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"22912405","pmcid":"PMC3437880","openalex_id":null,"authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"R01 CA140188","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"X01MH083259-01","title":null},{"funder_name":"NIA NIH HHS","grant_id":"AG031300","title":null},{"funder_name":"NIA NIH HHS","grant_id":"K01 AG031300","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA140188","title":null},{"funder_name":"Intramural NIH HHS","grant_id":"","title":null}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"bronze","license":null,"oa_locations":[{"url":"https://www.pnas.org/content/pnas/109/36/14592.full.pdf","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.1200037109","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":["Jurkat Cells","Animals","Zebrafish","Humans","Mice","Benzodiazepines","Blotting, Western","Electrophoretic Mobility Shift Assay","Flow Cytometry","Fluorescence Resonance Energy Transfer","Surface Plasmon Resonance","Histological Techniques","Immunoprecipitation","Protein Interaction Mapping","Hematopoiesis","Amino Acid Sequence","Genetic Vectors","Molecular Sequence Data","Core Binding Factor beta Subunit","Core Binding Factor Alpha 2 Subunit","Leukemia, Myeloid, Acute","Precursor Cell Lymphoblastic Leukemia-Lymphoma","Transcriptional Activation","High-Throughput Screening Assays"],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T16:05:32.893014Z","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":[]}