Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach

Huaqing Cui, Zeeshan Kamal, Teng Ai, Yanli Xu, Swati S. More, Daniel J. Wilson, Liqiang Chen

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD+-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD+. Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.

Original languageEnglish (US)
Pages (from-to)8340-8357
Number of pages18
JournalJournal of medicinal chemistry
Issue number20
StatePublished - Oct 23 2014

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© 2014 American Chemical Society.

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