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

Matthias Schiedel, Daniel Herp, Sören Hammelmann, Sören Swyter, A. Lehotzky, Dina Robaa, J. Oláh, J. Ovádi, Wolfgang Sippl, Manfred Jung

Research output: Contribution to journalArticle

71 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)482-491
Number of pages10
JournalJournal of Medicinal Chemistry
Volume61
Issue number2
DOIs
Publication statusPublished - Jan 25 2018

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this