Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders
Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode of action. In this work, we report the design, synthesis, and biological evaluation of the first-in-class selective degraders of the class IIb histone deacetylases (HDACs) 6 and 10. To this end, the dual HDAC6/10 inhibitor tubastatin A and a ring-opened analog were connected via well-established PROTAC linkers to pomalidomide and phenylglutarimides as cereblon recruiters. This approach led to the discovery of <b>AP1</b> (HDAC6 DC<sub>50</sub> = 13 nM; HDAC10 DC<sub>50</sub> = 29 nM) as a potent degrader of class IIb HDACs. Importantly, <b>AP1</b> neither degraded HDAC1/8 (class I) and HDAC4/7 (class IIa), nor induced histone H3 hyperacetylation, thereby confirming its selectivity for class IIb HDACs. Due to its low cytotoxicity against hematological and solid cancer cell lines, <b>AP1</b> represents a valuable tool compound for the chemical knockdown of class IIb HDACs.
Authors
- Bjoern B. Burckhardt (ORCID: https://orcid.org/0000-0002-1782-9937)
- Rabea Voget (ORCID: https://orcid.org/0009-0003-9249-8773)
- Philipp König (ORCID: https://orcid.org/0000-0002-6535-6599)
- Linda Schäker‐Hübner (ORCID: https://orcid.org/0000-0001-7734-124X)
- Gerd Bendas (ORCID: https://orcid.org/0000-0002-8667-7201)
- Michael Gütschow (ORCID: https://orcid.org/0000-0002-9376-7897)
- Finn K. Hansen (ORCID: https://orcid.org/0000-0001-9765-5975)
- Dominika Ewa Pieńkowska
- Shiyang Zhai (ORCID: https://orcid.org/0009-0005-6840-3177)
- Maria Hanl
- Felix Meissner (ORCID: https://orcid.org/0000-0003-1000-7989)
- Lukas Jacobi
- Radosław P. Nowak (ORCID: https://orcid.org/0000-0002-0605-0071)
- Christian Steinebach (ORCID: https://orcid.org/0000-0001-5638-1955)
- Irina Honin (ORCID: https://orcid.org/0009-0009-7091-8419)
- Jan Gerhartz (ORCID: https://orcid.org/0009-0002-9457-4656)
- Finn Dressler
Institutions
- University of Bonn (DE)
- University of Münster (DE)
- Innate Pharma (France) (FR)
- Pharmac (NZ)
- Institute of Structural and Molecular Biology (GB)
- Chemical Pharmaceutical Research Institute (BG)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00674
- Citations
- 6
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- Deutsche Forschungsgemeinschaft
- China Scholarship Council