{"doi":"10.3389/fphar.2024.1394685","title":"Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells","abstract":"Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to a significant reduction in colony formation, lipid storage, acetyl-CoA levels and cell survival in vitro . In an ex vivo brain-tumor slice model, treatment with AD-8007 and AD-5584 reduced pre-formed tumors and synergized with irradiation in blocking BCBM tumor growth. Treatment with AD-8007 reduced tumor burden and extended survival in vivo . This study identifies selective brain-penetrant ACSS2 inhibitors with efficacy towards breast cancer brain metastasis.","journal":"Frontiers in Pharmacology","year":2024,"id":424174,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"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":344702,"name":"Lorela Ciraku","orcid":"0009-0004-0602-3534","position":1,"is_corresponding":false},{"id":1026460,"name":"Riley G. Young","orcid":"0009-0003-5654-8526","position":2,"is_corresponding":false},{"id":1174458,"name":"Jessica Merzy","orcid":null,"position":3,"is_corresponding":false},{"id":1174459,"name":"Alexandra N. Talarico","orcid":null,"position":4,"is_corresponding":false},{"id":1221091,"name":"Nusaiba N. Ahmed","orcid":null,"position":5,"is_corresponding":false},{"id":1221092,"name":"Mangalam Karuppiah","orcid":null,"position":6,"is_corresponding":false},{"id":1221093,"name":"Anna Ramesh","orcid":null,"position":7,"is_corresponding":false},{"id":1015886,"name":"Adam Chatoff","orcid":"0000-0002-7954-9527","position":8,"is_corresponding":false},{"id":1220490,"name":"Claudia V. Crispim","orcid":"0000-0003-3422-1568","position":9,"is_corresponding":false},{"id":350332,"name":"Adel A. Rashad","orcid":"0000-0001-6113-0333","position":10,"is_corresponding":false},{"id":345789,"name":"Simon Cocklin","orcid":"0000-0002-9074-741X","position":11,"is_corresponding":false},{"id":237765,"name":"Nathaniel W. Snyder","orcid":"0000-0001-5643-8747","position":12,"is_corresponding":false},{"id":390877,"name":"Joris Beld","orcid":"0000-0001-7070-663X","position":13,"is_corresponding":false},{"id":237258,"name":"Nicole L. Simone","orcid":"0000-0002-7662-7470","position":14,"is_corresponding":false},{"id":344706,"name":"Mauricio J. Reginato","orcid":"0000-0002-7541-4094","position":15,"is_corresponding":false},{"id":275229,"name":"Alexej Dick","orcid":"0000-0003-0580-1897","position":16,"is_corresponding":false},{"id":1027312,"name":"Emily M. Esquea","orcid":null,"position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T01:58:07.191194Z","pmid":"38818373","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":[]}