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.
- 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.
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.