No abstract

Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis...

Histone deacetylases (HDACs) remove acetyl groups from histone proteins and are implicated in gene regulation. They have been recognized as drug targets for treatment of cancer and other human diseases and several inhibitors are already clinically used. Here, we report the design, synthesis, and cellular characterization of a proteolysis-targeting chimera (PROTAC) capable of selectively degrading class I HDACs 1–3 in cells. These novel chemotypes are based on potent and class I-selective macrocyclic tetrapeptide inhibitors, which were linked to thalidomide by modular synthesis, employing copper-catalyzed azide–alkyne “click” chemistry. In HEK293T cells, these conjugates lead to degradation of HDAC1–3 in a time- and concentration-dependent manner. Concomitant histone hyperacetylation without leading to cytotoxic effects was observed by western blot. These chemotypes enable the study of the biological roles of class I HDAC enzymes by short-term temporal deletion. Our compounds represent the first examples of degraders with demonstrated selectivity for class I HDACs 1–3. Importantly, this study highlights the utility of cyclic peptides as target-binding elements for PROTAC design in general.

New Thailandepsin B pseudo‐natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium‐catalyzed hydrooxycarbonylation. The newly developed pseudo‐natural products are extremely potent and selective HDAC inhibitors. The non‐proteinogenic amino acid d ‐norleucine was obtained enantioselectively by a recently developed method of rhodium‐catalyzed hydroamination.

The tubulin deacetylases Sirt2 and HDAC6 have been associated with the development of various diseases. Herein, we discuss recent approaches that enable cellular target engagement studies for these deacetylases and thus play a critical role in the evaluation of small molecule inhibitors of Sirt2 or HDAC6 as potential therapeutic agents.