{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T18:47:14Z","timestamp":1782413234667,"version":"3.54.5"},"reference-count":29,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM142505"],"award-info":[{"award-number":["R35GM142505"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2026,6,26]]},"abstract":"<jats:p>\n                    Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that regulates diverse cytosolic acetylation through its two catalytic deacetylase domains and a C\u2010terminal zinc finger ubiquitin\u2010binding domain (ZnF\u2010UBD). This ZnF\u2010UBD mediates key protein\u2013protein interactions (PPIs) that couple deacetylation and ubiquitin\u2010dependent degradation. While most HDAC6 inhibitors target the catalytic domains, the ZnF\u2010UBD represents an underexplored target. Here, we validate previously reported small\u2010molecule inhibitors of the HDAC6 ZnF\u2010UBD\/ubiquitin interaction and describe novel N\u2010alkyl moieties based on quinazolinone and phthalazinone scaffolds. Starting from known quinazolinone and phthalazinone scaffolds, a literature and modeling\u2010guided scaffold hop revealed potential for an extended phthalazinone series. Results obtained both in fluorescence polarization (FP) and differential scanning fluorimetry (DSF) confirm this hypothesis. Additionally, late\u2010stage diversification yields compounds with improved predicted physicochemical properties. Finally, machine\u2010learning\u2010based co\u2010folding affinity predictions correlate with experimental IC\n                    <jats:sub>50<\/jats:sub>\n                    rank order, highlighting their utility in PPI inhibitor design. These studies continue expanding the chemical space of HDAC6 ZnF\u2010UBD inhibitors and build upon existing foundations for future therapeutic and mechanistic exploration of HDAC6\u2013ubiquitin signaling.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70423","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T10:50:04Z","timestamp":1782298204000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quinazolinone and Phthalazinone Inhibitors of the HDAC6\/Ubiquitin Protein\u2013Protein Interaction"],"prefix":"10.1002","volume":"27","author":[{"given":"Sydney","family":"Gordon","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics University of Pennsylvania  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4621-0711","authenticated-orcid":false,"given":"Jordi C. 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