Selective inhibitors of SIRT2 regulate perinuclear α-tubulin acetylation, migration, and invasion of breast cancer cells

Sirtuin 2 (SIRT2) is a protein deacylase enzyme that has been reported to remove both acetyl groups and longer chain acyl groups from lysine residues in post-translationally modified proteins. 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 good chemical tool compounds are essential for the continued investigation of the complex function of this enzyme. Here, we report a collection of probes that are potent, selective, stable in serum, water soluble, amenable to cell culture experiments, and inhibit both SIRT2 deacetylation and demyristoylation. 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 applications in the interrogation of SIRT2 functions in both healthy and diseased cells to provide a foundation for the development of new therapeutics in the future.