Issue 2, 2021

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

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.

Graphical abstract: 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

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Article information

Article type
Paper
Submitted
28 3月 2020
Accepted
21 12月 2020
First published
14 1月 2021
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2021,2, 612-626

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

A. L. Nielsen, N. Rajabi, N. Kudo, K. Lundø, C. Moreno-Yruela, M. Bæk, M. Fontenas, A. Lucidi, A. S. Madsen, M. Yoshida and C. A. Olsen, RSC Chem. Biol., 2021, 2, 612 DOI: 10.1039/D0CB00036A

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