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

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.