HaloTag-Targeted Sirtuin-Rearranging Ligand (SirReal) for the Development of Proteolysis-Targeting Chimeras (PROTACs) against the Lysine Deacetylase Sirtuin 2 (Sirt2)** |
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| Authors: | Dr. Matthias Schiedel Dr. Attila Lehotzky Dr. Sandor Szunyogh Dr. Judit Oláh Sören Hammelmann Nathalie Wössner Dr. Dina Robaa Prof. Dr. Oliver Einsle Prof. Dr. Wolfgang Sippl Prof. Dr. Judit Ovádi Prof. Dr. Manfred Jung |
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| Affiliation: | 1. Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany;2. Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok körútja 2, 1117 Budapest, Hungary;3. Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany;4. Institute of Pharmacy, Martin-Luther-University Halle–Wittenberg, Kurt-Mothes-Straße 3, 06120 Halle/Saale, Germany;5. Institute of Biochemistry and BIOSS Centre for Biological Signalling Studies, University of Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany |
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| Abstract: | We have discovered the sirtuin-rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+-dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so-called proteolysis-targeting chimera (PROTAC) enabled small-molecule-induced degradation of Sirt2. Herein, we report the structure-based development of a chloroalkylated SirReal that induces the degradation of Sirt2 mediated by Halo-tagged E3 ubiquitin ligases. Using this orthogonal approach for Sirt2 degradation, we show that other E3 ligases than cereblon, such as the E3 ubiquitin ligase parkin, can also be harnessed for small-molecule-induced Sirt2 degradation, thereby emphasizing the great potential of parkin to be used as an E3 ligase for new PROTACs approaches. Thus, our study provides new insights into targeted protein degradation in general and Sirt2 degradation in particular. |
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| Keywords: | epigenetics HDACs PROTAC protein degradation sirtuins |
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