{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:02:00Z","timestamp":1787508120661,"version":"build-2736575974"},"reference-count":70,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Association for Cancer Research","award":["IG24449"],"award-info":[{"award-number":["IG24449"]}]},{"name":"Italian Association for Cancer Research","award":["P2022THN5N"],"award-info":[{"award-number":["P2022THN5N"]}]},{"name":"Italian Association for Cancer Research","award":["DOT13C5773-1"],"award-info":[{"award-number":["DOT13C5773-1"]}]},{"name":"PRIN PNRR 2022","award":["IG24449"],"award-info":[{"award-number":["IG24449"]}]},{"name":"PRIN PNRR 2022","award":["P2022THN5N"],"award-info":[{"award-number":["P2022THN5N"]}]},{"name":"PRIN PNRR 2022","award":["DOT13C5773-1"],"award-info":[{"award-number":["DOT13C5773-1"]}]},{"name":"PON \u201cRicerca e Innovazione\u201d 2014\u20132020","award":["IG24449"],"award-info":[{"award-number":["IG24449"]}]},{"name":"PON \u201cRicerca e Innovazione\u201d 2014\u20132020","award":["P2022THN5N"],"award-info":[{"award-number":["P2022THN5N"]}]},{"name":"PON \u201cRicerca e Innovazione\u201d 2014\u20132020","award":["DOT13C5773-1"],"award-info":[{"award-number":["DOT13C5773-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its multifunctional nature and overexpression in several cancer types, HDAC6 has emerged as a promising therapeutic target. Methods: In this study, we employed a ligand-based pharmacophore modeling approach using a structurally diverse set of known HDAC6 inhibitors. This was followed by the virtual screening of over 140,000 commercially available compounds from both the MolPort and Asinex databases. The screening workflow incorporated pharmacophore filtering, molecular docking, and molecular dynamic (MD) simulations. Binding free energies were estimated using Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis to prioritize top candidates. A fluorometric enzymatic assay was used to measure HDAC6 activity, while cell viability assay by Cell Titer Glo was used to assess the anti-tumor activity against drug-sensitive and -resistant multiple myeloma (MM) cells. Western blotting was used to evaluate the acetylation of tubulin or histone H4 after treatment with selected compounds. Results: Three promising compounds were identified based on stable binding conformations and favorable interactions within the HDAC6 catalytic pocket. Among them, Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis identified Compound 10 (AKOS030273637) as the top theoretical binder, with a \u0394Gbind value of \u221245.41 kcal\/mol. In vitro enzymatic assays confirmed its binding to the HDAC6 catalytic domain and inhibitory activity. Functional studies on MM cell lines, including drug-resistant variants, showed that Compound 10 reduced cell viability. Increased acetylation of \u03b1-tubulin, a substrate of HDAC6, likely suggested on-target mechanism of action. Conclusions: Compound 10, featuring a benzyl 4-[4-(hydroxyamino)-4-oxobutylidene] piperidine-1-carboxylate scaffold, demonstrates potential drug-like properties and a predicted bidentate zinc ion coordination, supporting its potential as an HDAC6 inhibitor for further development in hematologic malignancies.<\/jats:p>","DOI":"10.3390\/ph18091303","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:18:15Z","timestamp":1756484295000},"page":"1303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of a Promising Hydroxyamino-Piperidine HDAC6 Inhibitor via Integrated Virtual Screening and Experimental Validation in Multiple Myeloma"],"prefix":"10.3390","volume":"18","author":[{"given":"Federica","family":"Chiera","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6818-5325","authenticated-orcid":false,"given":"Antonio","family":"Curcio","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0680-7097","authenticated-orcid":false,"given":"Roberta","family":"Rocca","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"},{"name":"Associazione CRISEA-Centro di Ricerca e Servizi Avanzati per l\u2019Innovazione Rurale, Localit\u00e0 Condoleo di Belcastro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia","family":"Valentino","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Hematology Unit, Azienda Ospedaliera Annunziata, 87100 Cosenza, Italy"},{"name":"Department of Pharmacy, Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0437-358X","authenticated-orcid":false,"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"},{"name":"Associazione CRISEA-Centro di Ricerca e Servizi Avanzati per l\u2019Innovazione Rurale, Localit\u00e0 Condoleo di Belcastro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4638-7760","authenticated-orcid":false,"given":"Anna","family":"Artese","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 Magna Gr\u00e6cia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12460","DOI":"10.1021\/acs.jmedchem.0c00830","article-title":"Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight","volume":"63","author":"Ho","year":"2020","journal-title":"J. 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