2. Academic Validation
  3. Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals)

Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals)

  • J Med Chem. 2018 Jan 25;61(2):482-491. doi: 10.1021/acs.jmedchem.6b01872.
Matthias Schiedel 1,  Daniel Herp 1,  Sören Hammelmann 1,  Sören Swyter 1,  Attila Lehotzky 2,  Dina Robaa 3,  Judit Oláh 2,  Judit Ovádi 2,  Wolfgang Sippl 3,  Manfred Jung 1 4
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
  • 2 Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
  • 3 Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
  • 4 Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg , Albertstraße 19, 79104 Freiburg im Breisgau, Germany.
PMID: 28379698 DOI: 10.1021/acs.jmedchem.6b01872
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.

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