{
  "abstract": "This work reports on a series of von Hippel-Lindau (VHL)-recruiting histone deacetylase 6 (HDAC6) PROTACs based on a vorinostat-inspired HDAC inhibitor. Systematic variations of the VHL ligand, the exit vector, and the linker architecture revealed that longer, semi-rigid linkers promoted efficient HDAC6 degradation. Compounds 12-15 emerged as potent HDAC6 degraders, with 15 exhibiting a half-maximal degradation value of 26 nM with 12 showing particularly rapid degradation kinetics. The lead compounds induced pronounced and preferential HDAC6 degradation in MM.1S and FLT3-ITD-positive MV4-11 cells. Notably, 13-15 displayed submicromolar antiproliferative activity in MV4-11 cells and significantly induced apoptosis. Compound 13 was markedly more active than its non-degrading control nc-13, despite nearly identical HDAC1 and HDAC6 inhibitory activities, which underscores the important contribution of targeted HDAC degradation to the antiproliferative activity. Overall, this study supports VHL-mediated targeted degradation as a promising strategy to translate HDAC6 targeting into pronounced antileukemic activity.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, Germany, 53121",
    "Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, Germany, 53121"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Martina Miranda"
    },
    {
      "affs": [
        0
      ],
      "name": "Maria Hanl"
    },
    {
      "affs": [
        0
      ],
      "name": "Nisha Setia"
    },
    {
      "affs": [
        1
      ],
      "name": "Sophie Spülbeck"
    },
    {
      "affs": [
        0
      ],
      "name": "Katrin Nekipelov"
    },
    {
      "affs": [
        0
      ],
      "name": "Helena Skalski"
    },
    {
      "affs": [
        0
      ],
      "name": "Hadi Alizadeh"
    },
    {
      "affs": [
        0
      ],
      "name": "David Oppermann"
    },
    {
      "affs": [
        0
      ],
      "name": "Gerd Bendas"
    },
    {
      "affs": [
        1
      ],
      "name": "Michael Gütschow"
    },
    {
      "affs": [
        0
      ],
      "name": "Finn K. Hansen",
      "orcid": "0000-0001-9765-5975"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/czvdsxh11z5yn.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010272/v1",
  "fulltext_url": null,
  "id": "czvdsxh11z5yn",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010272/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7221565460",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010272/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-12",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/czvdsxh11z5yn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:22Z",
      "native_id": "10.26434/chemrxiv.15010272",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010272/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation",
  "title_text": "Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:22Z",
  "url": "https://research.draconitic.com/paper/czvdsxh11z5yn",
  "venue": "ChemRxiv",
  "versions": []
}