1 research outputs found
Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure–Activity Relationship Analysis
SIRT2, which is a
NAD+ (nicotinamide adenine dinucleotide) dependent
deacetylase, has been demonstrated to play an important role in the
occurrence and development of a variety of diseases such as cancer,
ischemia-reperfusion, and neurodegenerative diseases. Small molecule
inhibitors of SIRT2 are thought to be potential interfering agents
for relevant diseases. Discovery of SIRT2 inhibitors has attracted
much attention recently. In this investigation, we adopted a consensus
docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural
optimization and structure–activity relationship (SAR) analysis
were then carried out on highly potent compounds with new scaffolds,
which led to the discovery of 2-((5-benzyl-5<i>H</i>-[1,2,4]triazino[5,6-<i>b</i>]indol-3-yl)thio)-<i>N</i>-(naphthalen-1-yl)acetamide
(<b>SR86</b>). This compound showed good activity against SIRT2
with an IC<sub>50</sub> value of 1.3 μM. <b>SR86</b> did
not exhibit activity against SIRT1 and SIRT3, implying a good selectivity
for SIRT2. In in vitro cellular assays, <b>SR86</b> displayed
very good antiviability activity against breast cancer cell line MCF-7.
In Western blot assays, <b>SR86</b> showed considerable activity
in blocking the deacetylation of α-tubulin, which is a typical
substrate of SIRT2. Collectively, because of the new scaffold structure
and good selectivity of <b>SR86</b>, it could serve as a promising
lead compound, hence deserving further studies