{"doi":"10.3390/ijms24054720","title":"Selectivity of Hydroxamate- and Difluoromethyloxadiazole-Based Inhibitors of Histone Deacetylase 6 In Vitro and in Cells","abstract":"Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family of enzymes due to its complex domain organization and cytosolic localization. Experimental data point toward the therapeutic use of HDAC6-selective inhibitors (HDAC6is) for use in both neurological and psychiatric disorders. In this article, we provide side-by-side comparisons of hydroxamate-based HDAC6is frequently used in the field and a novel HDAC6 inhibitor containing the difluoromethyl-1,3,4-oxadiazole function as an alternative zinc-binding group (compound 7). In vitro isotype selectivity screening uncovered HDAC10 as a primary off-target for the hydroxamate-based HDAC6is, while compound 7 features exquisite 10,000-fold selectivity over all other HDAC isoforms. Complementary cell-based assays using tubulin acetylation as a surrogate readout revealed approximately 100-fold lower apparent potency for all compounds. Finally, the limited selectivity of a number of these HDAC6is is shown to be linked to cytotoxicity in RPMI-8226 cells. Our results clearly show that off-target effects of HDAC6is must be considered before attributing observed physiological readouts solely to HDAC6 inhibition. Moreover, given their unparalleled specificity, the oxadiazole-based inhibitors would best be employed either as research tools in further probing HDAC6 biology or as leads in the development of truly HDAC6-specific compounds in the treatment of human disease states.","journal":"International Journal of Molecular Sciences","year":2023,"id":326086,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":920985,"name":"Ivan Šnajdr","orcid":"0000-0002-0831-4034","position":1,"is_corresponding":false},{"id":1045661,"name":"Jiří Schimer","orcid":null,"position":2,"is_corresponding":false},{"id":649360,"name":"Zsófia Kutil","orcid":"0000-0001-9936-9518","position":3,"is_corresponding":false},{"id":1044932,"name":"Jana Mikešová","orcid":"0000-0001-6715-6614","position":4,"is_corresponding":false},{"id":316175,"name":"Petra Baranová","orcid":null,"position":5,"is_corresponding":false},{"id":315106,"name":"Barbora Havlínová","orcid":"0000-0002-2357-3763","position":6,"is_corresponding":false},{"id":1045662,"name":"W. TUECKMANTEL","orcid":null,"position":7,"is_corresponding":false},{"id":228371,"name":"Pavel Majer","orcid":"0000-0002-1804-6934","position":8,"is_corresponding":false},{"id":318196,"name":"Alan P. Kozikowski","orcid":"0000-0003-4795-5368","position":9,"is_corresponding":false},{"id":315109,"name":"Cyril Bařinka","orcid":"0000-0003-2751-3060","position":10,"is_corresponding":false},{"id":315101,"name":"J. Ptáček","orcid":"0000-0002-9099-6387","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T01:08:33.106703Z","pmid":"36902164","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":[]}