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Proteolysis-Targeting Chimeras (PROTACs) Based on Macrocyclic Tetrapeptides Selectively Degrade Class I Histone Deacetylases 1–3

submitted on 03.06.2020, 10:11 and posted on 04.06.2020, 06:38 by Martin Roatsch, Anja Vogelmann, Daniel Herp, Manfred Jung, Christian Adam Olsen
Histone deacetylases (HDACs) remove acetyl groups from histone proteins and are implicated in gene regulation. They have been recognized as drug targets for treatment of cancer and other human diseases and several inhibitors are already clinically used. Here, we report the design, synthesis, and cellular characterization of a proteolysis-targeting chimera (PROTAC) capable of selectively degrading class I HDACs 1–3 in cells. These novel chemotypes are based on potent and class I-selective macrocyclic tetrapeptide inhibitors, which were linked to thalidomide by modular synthesis, employing copper-catalyzed azide–alkyne “click” chemistry. In HEK293T cells, these conjugates lead to degradation of HDAC1–3 in a time- and concentration-dependent manner. Concomitant histone hyperacetylation without leading to cytotoxic effects was observed by western blot. These chemotypes enable the study of the biological roles of class I HDAC enzymes by short-term temporal deletion. Our compounds represent the first examples of degraders with demonstrated selectivity for class I HDACs 1–3. Importantly, this study highlights the utility of cyclic peptides as target-binding elements for PROTAC design in general.


Deutsche Forschungsgemeinschaft, RO5526/1-1

Deutsche Forschungsgemeinschaft, Project ID 192904750

Lundbeck Foundation, R289-2018-2074t

Carlsberg Foundation, CF15-011


Email Address of Submitting Author


University of Copenhagen



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no conflict of interest