Sirtuins catalyze the deacetylation of Ac-Lys residues of proteins using NAD+ as a cofactor. There are seven distinct sirtuin gene products (SIRT1-7). SIRT2 mainly deacetylates a-tublin regulating cell cycle progression. Recently, it was reported that SIRT2 causes neuron cell death in neurodegenerative diseases. Therefore, SIRT2-selective inhibitors may act as new remedies for neurodegenerative diseases as well as biological reagent to reveal the detailed functions of SIRT2.We designed and prepared a series of 2-anilinobenzamide analogues based on the homology model of SIRT1 and SIRT2. Enzyme assays using SIRT1 and SIRT2 revealed that several analogues are potent and selective SIRT2 inhibitors. These analogues also caused a dose-dependent selective increase of a-tubulin acetylation in human colon cancer HCT116 cells, indicating selective inhibition of SIRT2 in the cells. Our findings indicate that 2-anilinobenzamide analogues represent an entry into a new class of SIRT2-selective inhibitors.

Discovery of SIRT2-selective inhibitors

243rd National Meeting (2012)

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