Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration. Issue 2 (14th January 2021)

• Record Type: Journal Article
• Authors: Nielsen, Alexander L.; Rajabi, Nima; Kudo, Norio; Lundø, Kathrine; Moreno-Yruela, Carlos; Bæk, Michael; Fontenas, Martin; Lucidi, Alessia; Madsen, Andreas S.; Yoshida, Minoru; Olsen, Christian A.
• Is Part Of: RSC chemical biology. Volume 2:Issue 2(2021)
• Page Start: 612
• Page End: 626
• Publication Date: 2021-01-14
• Subjects: 572
• DOI: 10.1039/d0cb00036a
• Languages: English
• ISSNs: 2633-0679

Abstract

Abstract : Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. Here, we developed small peptide-based inhibitors of its activity in living cells in culture. Abstract : Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of chemical probes that are potent, selective, stable in serum, water-soluble, and inhibit SIRT2-mediated deacetylation and demyristoylation in cells. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics.