{"doi":"10.1021/acs.jmedchem.4c01817","title":"Hydrazide-Based Class I Selective HDAC Inhibitors Completely Reverse Chemoresistance Synergistically in Platinum-Resistant Solid Cancer Cells","abstract":"In this work, we have synthesized a set of peptoid-based histone deacetylase inhibitors (HDACi) with a substituted hydrazide moiety as zinc-binding group. Subsequently, all compounds were evaluated in biochemical HDAC inhibition assays and for their antiproliferative activity against native and cisplatin-resistant cancer cell lines. The hydrazide derivatives with a propyl or butyl substituent (compounds <b>5</b> and <b>6</b>) emerged as the most potent class I HDAC selective inhibitors (HDAC1-3). Further, compounds <b>5</b> and <b>6</b> outperformed entinostat in cytotoxicity assays and were able to reverse chemoresistance in cisplatin-resistant A2780 (ovarian) and Cal27 (head-neck) cancer cell lines. Moreover, the hydrazide derivatives <b>5</b> and <b>6</b> showed strong synergism with cisplatin (combination indices <0.2), again outperforming entinostat, and increased DNA damage, p21, and pro-apoptotic BIM expression, leading to caspase-mediated apoptosis and cell death. Thus, compounds <b>5</b> and <b>6</b> represent promising lead structures for developing new HDACi capable of reversing chemoresistance in cisplatin resistant cancer cells.","journal":"Journal of Medicinal Chemistry","year":2024,"id":12745,"datarank":0.5391848832739503,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.09751903639898415,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.09751903639898415,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":11,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0486,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-10-02","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":99066,"name":"Lukas Biermann","orcid":null,"position":1,"is_corresponding":false},{"id":99067,"name":"Linda Schäker-Hübner","orcid":null,"position":2,"is_corresponding":false},{"id":99068,"name":"Maria Hanl","orcid":null,"position":3,"is_corresponding":false},{"id":99069,"name":"Alexandra Hamacher","orcid":null,"position":4,"is_corresponding":false},{"id":99070,"name":"Matthias U. Kassack","orcid":"0000-0002-9094-8481","position":5,"is_corresponding":false},{"id":99071,"name":"Finn K. Hansen","orcid":"0000-0001-9765-5975","position":6,"is_corresponding":false},{"id":99072,"name":"Linda Schäker‐Hübner","orcid":"0000-0001-7734-124X","position":7,"is_corresponding":false},{"id":99065,"name":"Fabian B. Kraft","orcid":"0009-0008-5764-433X","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}