{"doi":"10.1530/erc-21-0085","title":"Inhibition of GATA2 in prostate cancer by a clinically available small molecule","abstract":"Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.","journal":"Endocrine Related Cancer","year":2021,"id":173853,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"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":712591,"name":"Aleksandra Rusin","orcid":null,"position":1,"is_corresponding":false},{"id":550500,"name":"Christopher Foley","orcid":"0000-0002-9028-5841","position":2,"is_corresponding":false},{"id":271397,"name":"Kimal Rajapakshe","orcid":"0000-0002-0472-858X","position":3,"is_corresponding":false},{"id":712592,"name":"Matthew Robertson","orcid":null,"position":4,"is_corresponding":false},{"id":712593,"name":"Darlene Skapura","orcid":null,"position":5,"is_corresponding":false},{"id":712594,"name":"Cammy Mason","orcid":null,"position":6,"is_corresponding":false},{"id":565233,"name":"Karen Berman de Ruiz","orcid":null,"position":7,"is_corresponding":false},{"id":712595,"name":"Alexey Mikhailovich Tyryshkin","orcid":null,"position":8,"is_corresponding":false},{"id":712596,"name":"Jenny Deng","orcid":null,"position":9,"is_corresponding":false},{"id":712597,"name":"Jin Na Shin","orcid":null,"position":10,"is_corresponding":false},{"id":304991,"name":"Warren Fiskus","orcid":"0000-0002-7343-6214","position":11,"is_corresponding":false},{"id":344542,"name":"Jianrong Dong","orcid":"0000-0001-5368-2787","position":12,"is_corresponding":false},{"id":2210,"name":"Shixia Huang","orcid":"0000-0003-2878-4129","position":13,"is_corresponding":false},{"id":712598,"name":"Nora M Navone","orcid":null,"position":14,"is_corresponding":false},{"id":712599,"name":"Christel M Davis","orcid":null,"position":15,"is_corresponding":false},{"id":712600,"name":"Erik A Ehli","orcid":null,"position":16,"is_corresponding":false},{"id":63736,"name":"Cristian Coarfa","orcid":"0000-0002-4183-4939","position":17,"is_corresponding":false},{"id":634910,"name":"Nicholas Mitsiades","orcid":"0000-0002-4659-476X","position":18,"is_corresponding":false},{"id":634911,"name":"Salma Kaochar","orcid":"0000-0001-9437-8829","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:46:49.903770Z","pmid":"34636746","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":[]}