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HaloTag-Targeted Sirtuin Rearranging Ligand (SirReal) for the Development of Proteolysis Targeting Chimeras (PROTACs) Against the Lysine Deacetylase Sirtuin 2 (Sirt2)

preprint
submitted on 26.05.2020 and posted on 27.05.2020 by Matthias Schiedel, Attila Lehotzky, Sándor Szunyogh, Judit Oláh, Sören Hammelmann, Nathalie Wössner, Dina Robaa, Oliver Einsle, Wolfgang Sippl, Judit Ovádi, Manfred Jung
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. Here, 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 also other E3 ligases than cereblon, such as the E3 ubiquitin ligase parkin, can be harnessed for small molecule-induced Sirt2 degradation, thereby emphasizing the great potential of parkin to be utilized 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.

Funding

Deutsche Forschungsgemeinschaft Ju295/14-1, RTG1976, Si868/14-1, SFB992

OTKA T-1122144

János Bolyai Research Scholarship of the Hungarian Academy of Sciences

History

Email Address of Submitting Author

manfred.jung@pharmazie.uni-freiburg.de

Institution

University of Freiburg

Country

Germany

ORCID For Submitting Author

0000-0002-6361-7716

Declaration of Conflict of Interest

No conflict of interest

Version Notes

Version 1.0 Original version

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