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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.<\/jats:p>","DOI":"10.3390\/ijms24054720","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T03:03:48Z","timestamp":1677639828000},"page":"4720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Selectivity of Hydroxamate- and Difluoromethyloxadiazole-Based Inhibitors of Histone Deacetylase 6 In Vitro and in Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9099-6387","authenticated-orcid":false,"given":"Jakub","family":"Ptacek","sequence":"first","affiliation":[{"name":"Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-4034","authenticated-orcid":false,"given":"Ivan","family":"Snajdr","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Schimer","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-9518","authenticated-orcid":false,"given":"Zsofia","family":"Kutil","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Mikesova","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Baranova","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Havlinova","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Tueckmantel","sequence":"additional","affiliation":[{"name":"StarWise Therapeutics LLC, University Research Park, Inc., Madison, WI 53719, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Majer","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Kozikowski","sequence":"additional","affiliation":[{"name":"StarWise Therapeutics LLC, University Research Park, Inc., Madison, WI 53719, USA"},{"name":"Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2751-3060","authenticated-orcid":false,"given":"Cyril","family":"Barinka","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1042\/bj20021321","article-title":"Histone deacetylases (HDACs): Characterization of the classical HDAC family","volume":"370","author":"Caron","year":"2003","journal-title":"Biochem. 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