2. Academic Validation
  3. Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders

Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders

  • J Med Chem. 2025 Jul 10;68(13):13793-13821. doi: 10.1021/acs.jmedchem.5c00674.
Shiyang Zhai 1,  Irina Honin 1,  Linda Schäker-Hübner 1,  Maria Hanl 1,  Lukas Jacobi 2,  Finn Dressler 3,  Dominika Ewa Pieńkowska 4,  Philipp König 1,  Jan Gerhartz 4,  Rabea Voget 5,  Gerd Bendas 1,  Michael Gütschow 5,  Felix Meissner 2,  Bjoern B Burckhardt 3,  Radosław P Nowak 4,  Christian Steinebach 5,  Finn K Hansen 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
  • 2 Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
  • 3 Individualized Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, 48149 Münster, Germany.
  • 4 Institute of Structural Biology, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
  • 5 Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
PMID: 40532131 DOI: 10.1021/acs.jmedchem.5c00674
Abstract

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 AP1 (HDAC6 DC50 = 13 nM; HDAC10 DC50 = 29 nM) as a potent degrader of class IIb HDACs. Importantly, AP1 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, AP1 represents a valuable tool compound for the chemical knockdown of class IIb HDACs.

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