title: Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals).
abstract: Here we report the development of a proteolysis targeting chimera (PROTAC) based on the combination of the unique features of the sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, a bona fide cereblon ligand. For the first time, we report the formation of a PROTAC by Cu(I)-catalyzed cycloaddition of a thalidomide-derived azide to an alkynylated inhibitor. This thalidomide-derived azide as well as the highly versatile linking strategy can be readily adapted to alkynylated ligands of other targets. In HeLa cells, our SirReal-based PROTAC induced isotype-selective Sirt2 degradation that results in the hyperacetylation of the microtubule network coupled with enhanced process elongation. Thus, our SirReal-based PROTAC is the first example of a probe that is able to chemically induce the degradation of an epigenetic eraser protein.
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiedel
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Herp
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Hammelmann
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Swyter
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Lehotzky
authors.affiliation: Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Oláh
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Ovádi
authors.affiliation: Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.|Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg , Albertstraße 19, 79104 Freiburg im Breisgau, Germany.
authors.forename: Manfred
authors.identifier: 0000-0002-6361-7716
authors.initials: M
authors.lastname: Jung
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D060326:Chemistry Techniques, Synthetic; D061565:Cycloaddition Reaction; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010447:Peptide Hydrolases / Q000737:chemistry; D059748:Proteolysis / Q000187:drug effects*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013792:Thalidomide / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D008024:Ligands; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; C474199:SIRT2 protein, human; D056565:Sirtuin 2