jm500777s_si_001.pdf (226.31 kB)
Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach
journal contribution
posted on 2014-10-23, 00:00 authored by Huaqing Cui, Zeeshan Kamal, Teng Ai, Yanli Xu, Swati S. More, Daniel J. Wilson, Liqiang ChenSirtuin
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.