{"doi":"10.1101/2021.04.19.440460","title":"Development of Small Molecule Inhibitors Targeting PBX1 Transcription Signaling as a Novel Cancer Therapeutic Strategy","abstract":"Abstract PBX1 (pre-B cell leukemia transcription factor 1) is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. PBX1 is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies including breast, lung, melanoma, and ovarian carcinomas. Cancer cells with elevated PBX1 signaling are particularly vulnerable to PBX1-withdrawal. We designed a series of small molecule compounds capable of docking to the interface between PBX1 and its cognate DNA target sequence and identified a lead compound, T417, which efficiently hindered the formation of the PBX1 transcriptional complex and affected the transcription of PBX1 target genes. In cell-based assays, T417 significantly suppressed long-term self-renewal and proliferation of cancer cells expressing high levels of PBX1 but not of those expressing low levels of PBX1. T417 also re-sensitized platinum-resistant ovarian tumor cells to carboplatin and produced synergistic anti-tumorigenic effects in vivo in combination with carboplatin. Normal tissues were spared, likely due to the lower PBX1 expression levels. Since PBX1 functions as a molecular hub in developing cancer recurrence and treatment resistance, our data highlight the potential of targeting the PBX-DNA interface as a therapeutic strategy for patients whose tumors rely on PBX1 activation for survival.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":220623,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":715002,"name":"Jin Gyoung Jung","orcid":"0000-0002-4296-4786","position":1,"is_corresponding":false},{"id":288410,"name":"Geoffrey D. Shimberg","orcid":"0000-0001-7986-0895","position":2,"is_corresponding":false},{"id":396816,"name":"Fang‐Chi Hsu","orcid":"0000-0001-6955-929X","position":3,"is_corresponding":false},{"id":288401,"name":"Yohan Suryo Rahmanto","orcid":"0000-0003-1453-7872","position":4,"is_corresponding":false},{"id":291321,"name":"Stéphanie Gaillard","orcid":"0000-0002-2174-3693","position":5,"is_corresponding":false},{"id":291315,"name":"Jiaxin Hong","orcid":"0009-0002-8864-3213","position":6,"is_corresponding":false},{"id":419613,"name":"Jürgen Bosch","orcid":"0000-0002-2624-4105","position":7,"is_corresponding":false},{"id":60420,"name":"Ie−Ming Shih","orcid":"0000-0002-1084-2071","position":8,"is_corresponding":false},{"id":291320,"name":"Chi-Mu Chuang","orcid":"0000-0001-6697-712X","position":9,"is_corresponding":false},{"id":39771,"name":"Tian‐Li Wang","orcid":"0000-0002-7082-449X","position":10,"is_corresponding":false},{"id":291314,"name":"Yao Shen","orcid":"0000-0002-4393-2794","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T23:53:46.965811Z","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":[]}